Submissions for variant NM_000059.4(BRCA2):c.9275A>T (p.Tyr3092Phe)

dbSNP: rs80359195

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167271	SCV000218113	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-04	criteria provided, single submitter	clinical testing	The p.Y3092F variant (also known as c.9275A>T), located in coding exon 24 of the BRCA2 gene, results from an A to T substitution at nucleotide position 9275. The tyrosine at codon 3092 is replaced by phenylalanine, an amino acid with highly similar properties. 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.
GeneDx	RCV000767170	SCV000566404	uncertain significance	not provided	2023-01-13	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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 9503A>T; This variant is associated with the following publications: (PMID: 12228710)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767170	SCV000600852	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560384	SCV000635732	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 3092 of the BRCA2 protein (p.Tyr3092Phe). This variant is present in population databases (rs80359195, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 91522). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167271	SCV000684047	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 3092 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250616 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483136	SCV000918964	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9275A>T (p.Tyr3092Phe) results in a conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250616 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9275A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002490671	SCV002782667	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-10-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474663	SCV004211917	uncertain significance	Familial cancer of breast	2023-09-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077039	SCV000108836	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-01-29	no assertion criteria provided	clinical testing