ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.396C>A (p.Asn132Lys) (rs80357413)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083203 SCV000244350 benign Breast-ovarian cancer, familial 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 = 0.000166
Invitae RCV001083972 SCV000076408 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000212156 SCV000209906 likely benign not specified 2016-06-29 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.
Ambry Genetics RCV000162966 SCV000213454 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: 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212156 SCV000538447 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 2/66738 European chromosomes; ClinVar: 3 labs B/LB, 1 lab VUS; at least 3 papers describe as non pathogenic
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000083203 SCV000576447 likely benign Breast-ovarian cancer, familial 1 2017-02-14 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000212156 SCV000586867 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162966 SCV000683141 likely benign Hereditary cancer-predisposing syndrome 2016-06-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587325 SCV000699090 benign not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.396C>A (p.Asn132Lys) variant (alternatively also known as 515C>A) involves the alteration of a non-conserved nucleotide and is not located in a known functional domain, while 4/5 in silico tools predict a damaging outcome for this variant. However, multiple functional studies demonstrated that this variant does not affect BRCA1 function (Towler_2013, Caligo_2009, Bouwman_2013, Maresca_2015, Thouvenot_2016). This variant was found in 2/121408 control chromosomes from ExAC at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in several HBOC patients without clear evidence supporting causality. The variant of interest was found to co-occur with another pathogenic BRCA2 variant, c.4936_4939delGAAA (p.Glu1646fxX23 - classified as pathogenic by LCA) has been reported, supporting a benign outcome. Multifactorial probability based model integrating multiple forms of genetic evidence indicates that the variant is benign (Lindor_2012 and Easton_2007). In addition, multiple clinical diagnostic laboratories/reputable databases/publications classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587325 SCV000887680 likely benign not provided 2019-06-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000083203 SCV001285179 likely benign Breast-ovarian cancer, familial 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000083203 SCV000115277 likely benign Breast-ovarian cancer, familial 1 2009-11-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083203 SCV000145271 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353495 SCV000591262 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Asn132Lys variant was identified in 1 of 552 proband chromosomes (frequency: 0.002) from Italian families with breast and ovarian cancer; and, functional assay(s) utilizing yeast based systems were discrepant; the variant was suggested to be neutral as it mapped outside the C-terminus domain; however, it was categorized as potentially deleterious, based on a significant induction of recombination in a yeast – HR (homologous recombination) based assay (Caligo 2008). In another functional assay measuring cell proliferation as an indicator of ability of the variant to compliment BRCA1 deficient mouse embryonic stem cells, the p.Asn132Lys variant was assessed to be neutral (Bouwman 2013). A third functional assay using HDR (homology directed recombination) to assess the 2 pathways of DNA repair BRCA1 is involved in: (DSB-double strand DNA breaks, and SSA – single strand annealing) showed that the variant had wildtype function in both assays, making it nonpathogenic (Towler 2013). Further, in a predictive posterior probability model that uses several sources of information to classify VUS, the variant was concluded to be nonpathogenic (Lindor 2012). The variant was identified in dbSNP (ID: rs80357413) “With other allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined The variant was also identified in dbSNP (ID: rs80357413s) “With likely benign allele”, Clinvitae database (2X as “benign” and 1X as “likely benign”), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (as no clinical significance), the ClinVar database (classified as “benign”), the BIC database (5X with unknown clinical importance), and UMD (4X with a “likely neutral” classification), Fanconi Anemia Mutation Database (LOVD) as likely neutral). The variant was also identified by the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 66738 (European (Non-Finnish)) alleles (frequency: 2.997E-05), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asn132residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; however, this information 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000083203 SCV000733674 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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