Submissions for variant NM_007294.4(BRCA1):c.3929C>A (p.Thr1310Lys)

gnomAD frequency: 0.00024  dbSNP: rs80357257

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048383	SCV000076396	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000589731	SCV000209964	uncertain significance	not provided	2024-02-20	criteria provided, single submitter	clinical testing	Observed in individuals with breast or pancreatic cancer, but also in unaffected controls (PMID: 30666157, 33471991, 35980532); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4048C>A; This variant is associated with the following publications: (PMID: 35980532, 18824701, 15385441, 31131967, 25348012, 33471991, 28717660, 30666157, 15343273, 22737296)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589731	SCV000605860	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569349	SCV000665800	likely benign	Hereditary cancer-predisposing syndrome	2021-08-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501619	SCV000699086	uncertain significance	not specified	2020-08-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation sites (PMID: 22193408). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 394484 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation (i.e. 51/48248 alleles) in the gnomAD database (v2.1 exomes dataset and v3 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. To our knowledge, the variant, c.3929C>A, has been reported in the literature in at least two individuals, who were affected with breast- and pancreatic carcinoma (Spearman_2008, Lovecek_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and six of them classified the variant as VUS, while one called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000083201	SCV000786541	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-22	criteria provided, single submitter	clinical testing
Mendelics	RCV003492386	SCV000839243	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569349	SCV000911049	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 1310 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 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000569349	SCV003847732	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).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003992170	SCV004811983	benign	Familial cancer of breast	2024-04-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083201	SCV004817725	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 1310 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 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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.
Sharing Clinical Reports Project (SCRP)	RCV000083201	SCV000115275	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083201	SCV000144917	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589731	SCV001553543	uncertain significance	not provided		no assertion criteria provided	clinical testing