Submissions for variant NM_000059.4(BRCA2):c.4850G>A (p.Ser1617Asn)

gnomAD frequency: 0.00001  dbSNP: rs397507341

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166443	SCV000217238	likely benign	Hereditary cancer-predisposing syndrome	2018-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV001703438	SCV000520481	likely benign	not provided	2018-04-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21232165, 21120943)
Invitae	RCV000697920	SCV000826554	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-04	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000697920	SCV000890913	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166443	SCV000906092	likely benign	Hereditary cancer-predisposing syndrome	2018-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000437440	SCV001442544	uncertain significance	not specified	2021-09-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4850G>A (p.Ser1617Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 356946 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4850G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stegel_2011, Dorling_2021) but it was also reported in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.3599_3600delGT, p.Cys1200X; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000166443	SCV002533908	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166443	SCV003852145	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703438	SCV004219659	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 21120943 (2011), 21232165 (2011)). Additionally, the variant has been reported in healthy, unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). The frequency of this variant in the general population, 0.000027 (3/113110 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000031509	SCV000054114	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-04	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000437440	SCV000587727	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research