Submissions for variant NM_007294.4(BRCA1):c.1105G>A (p.Asp369Asn)

gnomAD frequency: 0.00001  dbSNP: rs56056711

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)	RCV000030971	SCV000244294	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000568
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047341	SCV000075354	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162972	SCV000213460	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001703430	SCV000515314	likely benign	not provided	2020-11-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 21990134, 15235020, 22753008, 16677609)
Counsyl	RCV000030971	SCV000785357	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162972	SCV000903485	benign	Hereditary cancer-predisposing syndrome	2016-06-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735458	SCV002043418	likely benign	Breast and/or ovarian cancer	2023-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226169	SCV003923031	benign	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1105G>A (p.Asp369Asn) results in a conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. 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 1.6e-05 in 251130 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1105G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports 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. A quantitative posterior probability model showed that posterior probability of being deleterious for this variant is 5.68x10e-6 (Lindor_2012). Six clinical diagnostic laboratories or submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=5, VUS n=1), including an expert panel classified this variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703430	SCV004222547	likely benign	not provided	2022-12-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030971	SCV000053562	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-01-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030971	SCV000144010	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000030971	SCV000863595	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358186	SCV001553857	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asp369Asn variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs56056711) as with other allele; in the ClinVar and Clinvitae databases as benign by ENIGMA, Ambry Genetics; as likely benign by GeneDx, Invitae,Sharing Clinical Report Project; and as uncertain significance by CHEO Genetics Diagnostic Laboratory and Breast Cancer Information Core. The variant was also identified in the LOVD 3.0 database 3X as predicted neutral, BIC Database 2X as clinical importance unknown, and in the ARUP Laboratories database as not pathogenic or of no clinical significance. The variant was identified in control databases in 4 of 245866 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 4 of 111388 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In one study, authors utilized amino acid conservation and residue properties to classify missense variants and found the p.Asp369Asn variant to be neutral or of little clinical significance (Abkevich 2004). The p.Asp369Asn residue is not conserved in mammals and four out of five 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.