Submissions for variant NM_000059.4(BRCA2):c.938C>T (p.Ser313Phe)

gnomAD frequency: 0.00001  dbSNP: rs397507428

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129312	SCV000184074	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-18	criteria provided, single submitter	clinical testing	The p.S313F variant (also known as c.938C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 938. The serine at codon 313 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with breast and prostate cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Isaacsson Velho P et al. Prostate, 2018 04;78:401-407). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV000129312	SCV000292221	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467684	SCV000549496	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 313 of the BRCA2 protein (p.Ser313Phe). This variant is present in population databases (rs397507428, gnomAD 0.007%). This missense change has been observed in individual(s) with prostrate cancer (PMID: 29368341). ClinVar contains an entry for this variant (Variation ID: 38238). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Counsyl	RCV000031821	SCV000786430	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251312	SCV001426858	uncertain significance	not specified	2020-07-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.938C>T (p.Ser313Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 233168 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.938C>T has been reported in the literature in individuals affected with breast cancer or prostate cancer (Tung_2014, Isaacsson_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000129312	SCV002532027	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129312	SCV003848147	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).
GeneDx	RCV003234932	SCV003933408	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1166C>T; This variant is associated with the following publications: (PMID: 32377563, 29884841, 31556562, 25186627, 29368341, 31853058, 31911673)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003234932	SCV004220651	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000043 (1/233168 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25186627 (2015)) and prostate cancer (PMID: 29368341 (2018)). The variant has also been reported in an individual with ovarian cancer, however it is unknown if this variant was observed in the somatic or germline state (PMID: 31556562 (2019)). 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.
All of Us Research Program, National Institutes of Health	RCV000031821	SCV004846839	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031821	SCV000054429	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-01-19	no assertion criteria provided	clinical testing