ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2522G>A (p.Arg841Gln) (rs80357337)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083060 SCV000075881 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132442 SCV000187536 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.
GeneDx RCV000047868 SCV000209940 likely benign not specified 2017-05-10 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047868 SCV000698964 benign not specified 2019-09-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2522G>A (p.Arg841Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 283280 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.2e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.2522G>A, has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Barker_1996, Borg_2010, Judkins_2005, Schoumacher_2001, Brianese_2018, Zuntini_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2126insA, [p.Phe709TyrfsX3; BRCA2 c.7069_7070delCT , p.Leu2357ValfsX2; BRCA1 c.5152+2T>G), providing supporting evidence for a benign role. Additionally, one publication reports the variant present in a breast cancer patient, but absent in her affected mother, while both patients had a different pathogenic BRCA1 mutation, suggesting lack of segregation of the variant with disease (Zuntini_2018). Two publications have conducted functional studies: one used minigene splicing assays (Anczukow_2008) and one used functional complementation assays in cultured mouse embryonic stem cells (Bouwman_2013), both of which showed no significant effect on function caused by the variant. Six 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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000083185 SCV000743414 likely benign Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000083185 SCV000744654 likely benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132442 SCV000902867 benign Hereditary cancer-predisposing syndrome 2015-11-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083185 SCV000115259 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083185 SCV000144467 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353648 SCV000591393 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg841Gln variant was identified in 2 of 4282 proband chromosomes (frequency: 0.0004) from individuals or families with hereditary breast and ovarian cancer (Borg 2010, Schoumacher 2001). The variant was also identified in dbSNP (ID: rs80357337) “With other allele”, Exome Aggregation Consortium (ExAC) database, HGMD 3X, the ClinVar database 5X with conflicting classifications (classified as benign (SCRP and Ambry Genetics), likely benign (GeneDx), and uncertain significance (BIC - 6X); UMD reported the variant (10X as a likely neutral variant) and the Exome Aggregation Consortium (ExAC) database in 5 of 66708 (European (Non-Finnish)) alleles (frequency: 0.00007495), 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. In UMD the variant was identified with two co-occurring pathogenic variants, a BRCA1 variant p.Phe709TyrfsX3, and a BRCA2 variant p.Leu2357ValfsX2 increasing the likelihood that the p.Arg841Gln variant does not have clinical significance. The p.Arg841 residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in orangutans, macaques, mice, dogs, cows, frogs and sea urchins, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In addition, functional studies based on the physiologic expression of the full length BRCA1 cDNA in mice (Bouwman 2013) and in silico studies (Capanu 2011) showed the variant to be neutral. One in 5 splicing software suggested that this variant may create an alternative 3' splice site (human splicing finder), but this information is not very predictive of pathogenicity. Lastly, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, the clinical significance of this variant could not be determined with absolute certainty although we would lean towards a more benign role for this variant. This variant meets our laboratory's criteria to be classified as likely benign.

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