Submissions for variant NM_000059.4(BRCA2):c.3662C>A (p.Ser1221Tyr)

dbSNP: rs397507313

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160066	SCV000210319	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Identified in an individual with familial breast cancer (Meindl et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3890C>A; This variant is associated with the following publications: (PMID: 26992456, 31131967, 11802209, 22193408, 9002670, 29884841, 32377563)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698137	SCV000826780	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1221 of the BRCA2 protein (p.Ser1221Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 11802209). ClinVar contains an entry for this variant (Variation ID: 37851). 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.
Color Diagnostics, LLC DBA Color Health	RCV000772742	SCV000906066	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000772742	SCV001182358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	The p.S1221Y variant (also known as c.3662C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 3662. The serine at codon 1221 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was detected in 1/989 hereditary breast and/or ovarian cancer probands from a German cohort (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160066	SCV001469424	uncertain significance	not provided	2019-10-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000160066	SCV002010380	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772742	SCV003846774	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317050	SCV004020969	uncertain significance	not specified	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3662C>A (p.Ser1221Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3662C>A has been reported as a VUS in the literature in individuals affected with breast cancer or with family history of breast cancer (examples: Kleibova_2019, Meindl_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.3700_3704delGTAAA, p.Val1234Glnfs), in at least one individual affected with unilateral female breast cancer (example: Kleiblova_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31050813, 11802209). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031432	SCV000054037	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-01-15	no assertion criteria provided	clinical testing