ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2987T>G (p.Leu996Arg) (rs80358545)

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Total submissions: 12
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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) RCV000113125 SCV001161613 benign Breast-ovarian cancer, familial 2 2019-06-18 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 = 0.000661
Invitae RCV000167829 SCV000072111 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130463 SCV000185328 likely benign Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
GeneDx RCV000044098 SCV000210584 likely benign not specified 2017-10-09 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.
Illumina Clinical Services Laboratory,Illumina RCV000113125 SCV000383669 uncertain significance Breast-ovarian cancer, familial 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000324539 SCV000383670 uncertain significance Fanconi anemia, complementation group D1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV000130463 SCV000688782 likely benign Hereditary cancer-predisposing syndrome 2016-12-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679165 SCV000805682 likely benign not provided 2017-12-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044098 SCV000918960 likely benign not specified 2019-02-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2987T>G (p.Leu996Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276496 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00075). c.2987T>G has been reported in the literature once in a cohort of 493 Australian patients with triple negative breast cancer (Wong-Brown_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA2 legacy name 4075delGT, c.3847_3848delGT, p.Val1283fsX2) in a patient affected with ovarian cancer with a family history significant for breast cancer in two sisters and in two nieces all of whom were positive for BRCA2 mutation (Root_2012). These data provide supporting evidence for a benign role of the variant. In addition, the variant has been reported twice in the FLOSSIES database in women older than age 70 years who have never had cancer, providing further supporting evidence for a benign role of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (5x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679165 SCV001133731 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing
Mendelics RCV000113125 SCV001139052 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113125 SCV000146156 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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