Submissions for variant NM_007294.4(BRCA1):c.5071A>G (p.Thr1691Ala)

dbSNP: rs397509219

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589379	SCV000292911	uncertain significance	not provided	2016-02-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5071A>G at the cDNA level, p.Thr1691Ala (T1691A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant, also known as BRCA1 5190A>G using alternate nomenclature, was reported to be associated with RNA similar to wild type in a study of splicing defects using stimulated lymphocytes (Houdayer 2012). BRCA1 Thr1691Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1691Ala occurs at a position that is conserved in mammals and is located within the BRCT1 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr1691Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573049	SCV000665875	likely benign	Hereditary cancer-predisposing syndrome	2020-03-31	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	RCV000573049	SCV000683246	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1691 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in homology-directed repair, subcellular localization and phosphopeptide binding assays (PMID: 30257991) and the variant retains intermediate activity in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in an individual affected with ovarian cancer (PMID 24504028). 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	RCV000589379	SCV000699197	uncertain significance	not provided	2016-07-12	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5071A>G (p.Thr1691Ala) variant involves the alteration of a conserved nucleotide located in BRCT domain. p.Thr1691Ala was predicted to destabilize the BRCT domain and could have a functional impact (Caputo_2012). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 3/5 splice prediction tools predict no significant impact on normal splicing, which was confirmed by RNA analysis in patient's T lymphoctes (Houdayer_2012). This variant is absent in 121146 control chromosomes. This variant has been reported in patients in literature or databases without convincing evidence supporting pathogenicity of this variant. Taken together, this variant is classified as VUS until more information is available.
Counsyl	RCV000662496	SCV000785015	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV001360741	SCV001556673	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-01	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 30209399, 30257991, 32546644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55371). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24504028, 34597585). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ala).
Baylor Genetics	RCV000662496	SCV004212706	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003607225	SCV004543878	uncertain significance	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: PM2_SUP
Brotman Baty Institute, University of Washington	RCV000662496	SCV001243460	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro