Submissions for variant NM_000059.4(BRCA2):c.10127C>G (p.Ser3376Ter)

dbSNP: rs1555290049

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587368	SCV000694496	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.10127C>G (p.Ser3376X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. However, this variant is located in the last exon in the gene, and other truncating variants located in this exon upstream of this variant have been classified as VUS or benign by our lab (p.Glu3316fsX2, VUS; p.Lys3326X, benign; p.Glu3342X, VUS; p.Ser3366fsX4, benign). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121162 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, the functional significance of this truncating variant located in the last exon is unknown, therefore it has been classified as a VUS until additional evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000775705	SCV000910120	likely benign	Hereditary cancer-predisposing syndrome	2017-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775705	SCV001177957	likely benign	Hereditary cancer-predisposing syndrome	2018-06-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001479993	SCV001684301	likely benign	Hereditary breast ovarian cancer syndrome	2023-09-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587368	SCV005624311	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	The BRCA2 c.10127C>G (p.Ser3376*) variant is predicted to cause the premature termination of BRCA2 protein synthesis. However, this variant is located in the terminal exon of the BRCA2 gene and is not expected to result in non-sense mediated decay (NMD). In the published literature, this variant has been reported in individuals with non-small cell lung cancer (PMID: 34632253 (2021)) and prostate cancer (PMID: 36922933 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant.