Associated disorders

The SMARCA4 gene is associated with an increased risk of autosomal dominant small-cell carcinoma of the ovary, hypercalcemic type. Additionally, the SMARCA4 gene has preliminary evidence supporting a correlation with rhabdoid tumor predisposition syndrome type 2 (RTPS2) (MedGen UID: 413749).

The SMARCA4 gene encodes a catalytic subunit of SWI/SNF complexes, which function as regulators of gene expression by remodeling chromatin to alter nucleosome conformation, making it more accessible to transcriptional activation.

SMARCA4—Small Cell Carcinoma of the Ovary, Hypercalcemic Type
MedGen UID: 489981

Clinical condition
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), which has also been referred to as malignant rhabdoid tumor of the ovary (MRTO), accounts for less than 1% of all ovarian cancer. This specific type of ovarian cancer can be distinguished from others by the presence hypercalcemia (seen in one-third of cases), early age of onset (average 25 years), and small, hyperchromatic cells with brisk mitotic activity. SCCOHT can be difficult to decipher from other ovarian cancers because there is significant pathology overlap with sex cord-stromal tumors, germ cell tumors, endometrial stromal sarcoma, and neuroblastoma, among others. SCCOHT can occur sporadically, though approximately 50% of cases are due to pathogenic variants in the SMARCA4 gene (PMID: 24752781, 24658001, 24658002, 24658004).

Recent data suggest that SMARCA4 may be associated with rhabdoid tumor predisposition syndrome (RTPS); however, this evidence is limited and emerging (PMID: 20137775, 21566516, 23775540). The most common known cause of hereditary rhabdoid tumors is RTPS due to pathogenic variants in the SMARCB1 gene (PMID: 23775540, 25494491).

RTPS is associated with an increased risk of developing rhabdoid tumors, which are rare, aggressive childhood cancers that form in the kidney (called malignant rhabdoid tumor, MRT) and central nervous system (called atypical/rhabdoid tumor, AT/RT). In comparison to sporadic isolated rhabdoid tumors, patients with RTPS have an increased risk of developing multiple tumors at younger ages, and schwannomas (peripheral nerve sheath tumors), which present primarily in adulthood (PMID: 25494491). The primary risk in individuals with pathogenic variants in SMARCA4 is the development of SCCOHT, though the risk for tumors at other sites is not currently well defined (PMID: 20137775).

An individual with a SMARCA4 pathogenic variant may not necessarily develop cancer in their lifetime; however, the risk for cancer is increased over the general population risk. Likewise, the same variant may also present differently, even among people within the same family. Lifetime cancer risks for individuals with SMARCA4 pathogenic variants are currently unclear.

Gene information
The protein encoded by SMARCA4 is part of the large, ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. This complex is thought to regulate transcription of certain genes by altering the chromatin structure around those genes NCBI Gene. Gene ID: 6597. Accessed September 26, 2015. If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

SCCOHT due to pathogenic variants in SMARCA4 has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Most cases of SCCOHT occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 25494491). An individual with a variant in SMARCA4 has a 50% risk of passing that variant on to offspring.

Specific surveillance and screening guidelines are not established for individuals with pathogenic variants in SMARCA4. One study suggested that women at risk for SMARCA4-associated SCCOHT consider thorough observation by MRI and sonograms of potentially affected organs and prophylactic oophorectomy when childbearing is complete (PMID: 25886974). The establishment of full medical management and surveillance guidelines is anticipated as more individuals with pathogenic variants in SMARCA4 are identified (PMID: 25494491).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though data regarding pathogenic SMARCA4 is limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding SMARCA4 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to consider implementing suggested surveillance recommendations, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.


Review date: September 2015

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
SMARCA4 NM_001128849.1