Submissions for variant NM_007294.4(BRCA1):c.4314C>G (p.Ala1438=)

gnomAD frequency: 0.00001  dbSNP: rs80356856

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112314	SCV000578286	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/).
Ambry Genetics	RCV000163736	SCV000214311	likely benign	Hereditary cancer-predisposing syndrome	2017-06-28	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	RCV000429199	SCV000533327	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000112314	SCV000743395	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112314	SCV000744616	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001461728	SCV001665636	likely benign	Hereditary breast ovarian cancer syndrome	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000429199	SCV005883104	likely benign	not specified	2024-12-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112314	SCV000145053	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2007-01-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356947	SCV001552251	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Ala1438= variant was not identified in the literature nor was it identified in the UMD-LSDB databases. The variant was identified in dbSNP (ID: rs80356856) “With Likely benign allele”, ClinVar (classified likely benign, reviewed by an expert panel (2017); submitters: likely benign by ENIGMA, Genome Diagnostics Laboratory (University Medical Center Utrecht), Ambry Genetics and GeneDx, and uncertain significance by BIC), and LOVD 3.0 (1X). The variant was identified in control databases in 2 of 246176 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), observed in the following population: European Non-Finnish in 2 of 111640 chromosomes (freq: 0.00002), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ala1438= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001356947	SCV001740508	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001356947	SCV001952553	likely benign	not provided		no assertion criteria provided	clinical testing