Submissions for variant NM_007294.4(BRCA1):c.3835G>A (p.Ala1279Thr)

gnomAD frequency: 0.00002  dbSNP: rs80357036

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082264	SCV000076361	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129501	SCV000184273	likely benign	Hereditary cancer-predisposing syndrome	2019-01-31	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.
GeneDx	RCV000435150	SCV000526552	likely benign	not specified	2016-10-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000435150	SCV000605854	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679693	SCV000806941	uncertain significance	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129501	SCV000902917	benign	Hereditary cancer-predisposing syndrome	2017-04-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000435150	SCV002064573	likely benign	not specified	2019-06-27	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129501	SCV003846004	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).
All of Us Research Program, National Institutes of Health	RCV000083198	SCV004817739	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083198	SCV000115272	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083198	SCV000144890	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357948	SCV001553561	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ala1279Thr variant was not identified in the literature nor was it identified in the GeneInsight-COGR, COSMIC, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80357036) as “With Uncertain significance, other allele”, ClinVar and Clinvitae (3x classified as uncertain significance by Invitae, Quest Diagnostics and BIC; 2x classified as likely benign by Ambry Genetics and GeneDx; 1x classified as benign by SCRP), LOVD 3.0 (5 entries classified as effect unknown or not classified), UMD-LSDB (2 entries, classification neutral, 1 entry with a co-occurring pathogenic variant), BIC Database (1 entry, clinical importance unknown) databases. The variant was identified in control databases in 4 of 245878 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 4 of 111354 chromosomes (freq: 0.000036), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ala1279Thr residue is not conserved in mammals; indeed a threonine residue is observed in Gorilla gorilla at this position. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.