Submissions for variant NM_000059.4(BRCA2):c.9190G>T (p.Asp3064Tyr)

dbSNP: rs80359177

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045743	SCV000073756	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 3064 of the BRCA2 protein (p.Asp3064Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52773). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Ambry Genetics	RCV000129844	SCV000184661	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The p.D3064Y variant (also known as c.9190G>T), located in coding exon 23 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9190. The aspartic acid at codon 3064 is replaced by tyrosine, an amino acid with highly dissimilar properties. Utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, this alteration was predicted to be neutral (Karchin R et al. Cancer Inform 2008; 6:203-16). This alteration has been reported in an individual with early-onset colorectal cancer (Maletzki C et al. Oncologist, 2019 07;24:877-882). This alteration demonstrated behavior similar to wildtype in a mouse embryonic stem cell survival assay (Biswas K et al. NPJ Genom Med, 2020 Dec;5:52). This amino acid position is not well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779948	SCV000916894	uncertain significance	not specified	2019-12-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9190G>T (p.Asp3064Tyr) results in a non-conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9190G>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer or suspected LS (Karchin_2008, Maletzki_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985620	SCV001133970	uncertain significance	not provided	2019-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129844	SCV001354223	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 3064 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Complementation and drug sensitivity assays in mouse ES cells reported this variant to be functional (PMID: 33293522). This variant has been reported in an individual affected with colorectal cancer (PMID: 30683709). 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	RCV000985620	SCV004170713	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Observed in an individual with adenocarcinoma of the cecum and appendix (Maletzki et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate no damaging effect: ability to rescue cell lethality and lack of sensitivity to DNA-damaging drugs in a mouse embryonic stem cell (mESC)-based assay (Biswas et al., 2020); Also known as 9418G>T; This variant is associated with the following publications: (PMID: 12228710, 19043619, 29884841, 32377563, 30683709, 33293522)
Baylor Genetics	RCV003473429	SCV004211955	uncertain significance	Familial cancer of breast	2023-09-14	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114063	SCV000147563	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing