Submissions for variant NM_000059.4(BRCA2):c.9275A>C (p.Tyr3092Ser)

dbSNP: rs80359195

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045773	SCV000073786	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-03-29	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA2 protein function (PMID: 24323938, 23108138, 29394989). This variant has been reported in individuals affected with breast cancer (PMID: 21120943, 24916970), as well as an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52799). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 3092 of the BRCA2 protein (p.Tyr3092Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine.
Ambry Genetics	RCV000569862	SCV000665053	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	The p.Y3092S variant (also known as c.9275A>C), located in coding exon 24 of the BRCA2 gene, results from an A to C substitution at nucleotide position 9275. The tyrosine at codon 3092 is replaced by serine, an amino acid with dissimilar properties. In a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted likely deleterious (Karchin R et al. Cancer Inform. 2008;6:203-16). Multiple studies found that this alteration had intermediate activity in a cell-based homology-directed DNA break repair (HDR) functional assay (Hart SN et al. Genet Med, 2019 01;21:71-80; Mesman RLS et al. Genet. Med., 2019 02;21:293-302; Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Guidugli L et al. Cancer Res., 2013 Jan;73:265-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569862	SCV001354225	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with serine at codon 3092 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Functional studies have reported the variant protein to have intermediate activity relative to wild-type BRCA2 in homology-directed DNA repair assays (PMID: 23108138, 29394989, 29988080), and increased sensitivity to cisplatin and no impact on cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 29988080). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001775564	SCV002013603	uncertain significance	not provided	2017-03-26	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23108138, 24323938, 19043619, 29394989, 29988080, 29884841)
All of Us Research Program, National Institutes of Health	RCV000077465	SCV004846148	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with serine at codon 3092 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported the variant protein to have intermediate activity compared to wild-type in a homology-directed DNA repair assay (PMID: 23108138, 29394989). This variant has been reported in an individual affected with breast cancer (PMID: 24916970) and at least one individual with personal or family history of breast and/or ovarian cancer (PMID: 21120943). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000077465	SCV000109263	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-12-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077465	SCV000147596	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing