Submissions for variant NM_007294.4(BRCA1):c.2491T>G (p.Tyr831Asp)

dbSNP: rs1060502350

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464267	SCV000549381	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-12	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 831 of the BRCA1 protein (p.Tyr831Asp). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409348). 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 BRCA1 protein function. 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.
GeneDx	RCV000481004	SCV000564726	uncertain significance	not provided	2014-10-28	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2491T>G at the cDNA level, p.Tyr831Asp (Y831D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Tyr831Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Tyr831Asp occurs at a position that is poorly conserved across species and is located in DNA-binding domain (Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Tyr831Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001524346	SCV001734161	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with aspartic acid at codon 831 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001524346	SCV003847625	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).
Ambry Genetics	RCV001524346	SCV005550052	likely benign	Hereditary cancer-predisposing syndrome	2024-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.