Submissions for variant NM_007294.4(BRCA1):c.1394A>G (p.Tyr465Cys)

dbSNP: rs876659885

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219459	SCV000276811	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-08	criteria provided, single submitter	clinical testing	The p.Y465C variant (also known as c.1394A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1394. The tyrosine at codon 465 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000219459	SCV000682956	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 465 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779853	SCV000916715	uncertain significance	not specified	2018-02-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1394A>G (p.Tyr465Cys) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was absent in 121380 control chromosomes (ExAC). 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.1394A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000801376	SCV000941150	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-26	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 232629). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 465 of the BRCA1 protein (p.Tyr465Cys).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000219459	SCV003851326	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).