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

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)	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 Health, Inc	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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001284951	SCV001471052	likely benign	none provided	2019-12-21	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