Submissions for variant NM_007294.4(BRCA1):c.1574T>C (p.Val525Ala)

dbSNP: rs879253902

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236949	SCV000292737	uncertain significance	not provided	2015-12-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1574T>C at the cDNA level, p.Val525Ala (V525A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). Using alternate nomenclature, this variant would be defined as BRCA1 1693T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val525Ala 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 Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val525Ala occurs at a position that is not conserved across species and is located within the DNA binding domain and in a region reported to interact with multiple proteins (Narod 2004, Paul 2014). 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 Val525Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193189	SCV001361884	uncertain significance	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1574T>C (p.Val525Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250234 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1574T>C has been reported in the literature in an individual affected with Breast and/or Ovarian Cancer (Singh_2018). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001362691	SCV001558721	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine with alanine at codon 525 of the BRCA1 protein (p.Val525Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 26911350, 29470806). ClinVar contains an entry for this variant (Variation ID: 245690). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002401917	SCV002710039	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-09	criteria provided, single submitter	clinical testing	The p.V525A variant (also known as c.1574T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1574. The valine at codon 525 is replaced by alanine, an amino acid with similar properties. This variant was detected in 1/141 patients with breast and/or ovarian cancer from India (Mannan AU et al. J Hum Genet, 2016 Jun;61:515-22). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002401917	SCV003851196	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).