Submissions for variant NM_007294.4(BRCA1):c.2503C>T (p.His835Tyr)

gnomAD frequency: 0.00001  dbSNP: rs751656678

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509855	SCV000608216	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-25	criteria provided, single submitter	clinical testing	The p.H835Y variant (also known as c.2503C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2503. The histidine at codon 835 is replaced by tyrosine, an amino acid with similar properties. This alteration, designated c.2622C>T (H835Y), was detected in a family with breast and ovarian cancer from a cohort of 251 Southern German families who were tested for BRCA1/2 mutations (Meyer P et al. Hum Mutat, 2003 Sep;22:259). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759507	SCV000888868	uncertain significance	not provided	2017-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509855	SCV000909342	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 835 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 been reported in a suspected hereditary breast and ovarian cancer family and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 12938098, 33471991; Leiden Open Variation Database DB-ID BRCA1_001931). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-segregation with a pathogenic covariant and family history of 1.1391 and 0.2744, respectively (PMID: 31131967). This variant has been identified in 2/282432 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792748	SCV000932064	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465695	SCV002760940	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509855	SCV003847618	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).
All of Us Research Program, National Institutes of Health	RCV004003582	SCV004818172	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 835 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 been reported in a suspected hereditary breast and ovarian cancer family and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 12938098, 33471991; Leiden Open Variation Database DB-ID BRCA1_001931). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-segregation with a pathogenic covariant and family history of 1.1391 and 0.2744, respectively (PMID: 31131967). This variant has been identified in 2/282432 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.