Submissions for variant NM_007294.4(BRCA1):c.4347A>G (p.Thr1449=)

gnomAD frequency: 0.00001  dbSNP: rs80356840

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112321	SCV000578185	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae	RCV001082944	SCV000076544	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000166538	SCV000217339	likely benign	Hereditary cancer-predisposing syndrome	2014-10-21	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.
GeneDx	RCV000048531	SCV000512309	likely benign	not provided	2020-08-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28179634, 17100994, 16949048, 12872263, 16267036, 28392550, 30702160, 28692638)
Color Diagnostics, LLC DBA Color Health	RCV000166538	SCV000683172	likely benign	Hereditary cancer-predisposing syndrome	2015-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000437448	SCV000699134	benign	not specified	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4347A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within East Asian control individuals in the gnomAD database (0.001) is close to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, in certain East Asian subpopulations the variant was observed with an even higher occurrence, e.g. in the Japanese control population it occurred with a frequency of 0.0087 (HGVD), strongly suggesting a benign role for the variant. c.4347A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Han 2006, Judkins 2005, Kim 2006, Lee 2003, Hwang 2017). However, in several of these publications the authors listed the variant of interest as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000112321	SCV000785875	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000437448	SCV001133582	benign	not specified	2019-05-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112321	SCV001283848	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sema4, Sema4	RCV000166538	SCV002538289	likely benign	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003952475	SCV004780990	likely benign	BRCA1-related condition	2021-10-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112321	SCV000145064	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2004-12-27	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355721	SCV001550678	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Thr1449= variant was identified in 7 of 3724 proband chromosomes (frequency: 0.002) from Korean and Malaysian individuals or families with breast cancer, sporadic or unselected for family history, and was not identified in 334 control chromosomes from healthy individuals (Han 2006, Kim 2006, Lee 2003). The variant was also identified in the following databases: dbSNP (ID: rs80356840) as “With other allele”, in ClinVar (likely benign, reviewed by an expert panel 2017; submitters: benign by BIC, likely benign by ENIGMA, Invitae, Ambry Genetics and GeneDx), in Clinvitae (4x), and BIC Database (1x, with no clinical importance, classification pending), and was not identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 22 of 277016 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 6464 chromosomes (freq: 0.0002), East Asian in 20 of 18866 chromosomes (freq: 0.001), and South Asian in 1 of 30758 chromosomes (freq: 0.00003); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, and Finnish populations. The p.Thr1449= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs 11 nucleotides from the 3’ end of exon 11 and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.