Submissions for variant NM_007294.4(BRCA1):c.5024C>T (p.Thr1675Ile)

gnomAD frequency: 0.00001  dbSNP: rs150729791

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV001003385	SCV001161596	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000031
Invitae	RCV001082424	SCV000289815	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000256063	SCV000296456	uncertain significance	not provided	2018-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000256063	SCV000321437	likely benign	not provided	2020-11-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies classified as functional in a saturation genome editing (SGE) assay for BRCA1 (Findlay 2018); Also known as 5143C>T; This variant is associated with the following publications: (PMID: 15998910, 26898890, 26941049, 30209399, 31131967, 32123317)
Ambry Genetics	RCV000570967	SCV000660957	likely benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000570967	SCV000908998	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1675 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). A functional study has reported that this variant does not impact BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in a breast cancer case-control study in one case and one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002857) and also in an individual affected with breast cancer and two suspected hereditary breast and ovarian cancer families (PMID: 15998910, 26898890, 26941049). This variant also has been reported with segregation and tumor pathology likelihood ratios for pathogenicity of 0.0025 and 0.4 respectively (PMID: 31131967). This variant has been identified in 1/251362 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.
Brotman Baty Institute, University of Washington	RCV001003385	SCV001241975	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro