Submissions for variant NM_007294.4(BRCA1):c.3524C>T (p.Ala1175Val)

dbSNP: rs1567791322

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779870	SCV000916741	uncertain significance	not specified	2019-10-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3524C>T (p.Ala1175Val) results in a non-conservative amino acid change located in the outside of any known functional domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251270 control chromosomes (gnomAD). 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.3524C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856180	SCV002290237	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-15	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) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 632683). 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 alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1175 of the BRCA1 protein (p.Ala1175Val).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003158112	SCV003851745	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	RCV003158112	SCV003998780	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The p.A1175V variant (also known as c.3524C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3524. The alanine at codon 1175 is replaced by valine, an amino acid with 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.