Submissions for variant NM_007294.4(BRCA1):c.527C>T (p.Thr176Met)

gnomAD frequency: 0.00001  dbSNP: rs587782747

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000475232	SCV000549332	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 176 of the BRCA1 protein (p.Thr176Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27163896). This variant is also known as 646C>T. ClinVar contains an entry for this variant (Variation ID: 409326). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000582697	SCV000688556	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 176 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in an individual affected with contralateral breast cancer (PMID: 27163896). This variant has been identified in 2/251452 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.
Fulgent Genetics, Fulgent Genetics	RCV000764127	SCV000895100	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582697	SCV001185784	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The p.T176M variant (also known as c.527C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 527. The threonine at codon 176 is replaced by methionine, an amino acid with similar properties. This alteration (designated as 646C>T) was detected in an individual with contralateral breast cancer (Pellegrino B et al. Acta Biomed, 2016 05;87:54-63). This amino acid position is poorly 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.
GeneDx	RCV001770345	SCV001994056	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Observed in an individual with bilateral breast cancer (Pellegrino et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 646C>T; This variant is associated with the following publications: (PMID: 9788437, 20215511, 27163896)
Sema4, Sema4	RCV000582697	SCV002537833	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001770345	SCV004219450	uncertain significance	not provided	2022-10-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251452 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with contralateral breast cancer (PMID: 27163896 (2016). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.