Total submissions: 40
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000083145 | SCV004101441 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-10-12 | reviewed by expert panel | curation | The c.8149G>T variant in BRCA2 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 2717 (p.Ala2717Ser). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met). This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18375895). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BS3, BS2, BP5_Very strong). |
Invitae | RCV000045431 | SCV000073444 | benign | Hereditary breast ovarian cancer syndrome | 2024-02-01 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000083145 | SCV000154080 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-03-05 | criteria provided, single submitter | literature only | |
Gene |
RCV000120361 | SCV000167406 | benign | not specified | 2013-11-26 | 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 | RCV000129099 | SCV000183810 | benign | Hereditary cancer-predisposing syndrome | 2014-11-19 | 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. |
Michigan Medical Genetics Laboratories, |
RCV000083145 | SCV000196011 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-11-03 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV000735609 | SCV000219404 | benign | Breast and/or ovarian cancer | 2023-04-17 | criteria provided, single submitter | clinical testing | |
Eurofins Ntd Llc |
RCV000120361 | SCV000226714 | benign | not specified | 2014-08-15 | criteria provided, single submitter | clinical testing | |
Vantari Genetics | RCV000129099 | SCV000267024 | likely benign | Hereditary cancer-predisposing syndrome | 2015-12-18 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV000083145 | SCV000383777 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 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. |
Illumina Laboratory Services, |
RCV000280295 | SCV000383778 | likely benign | Fanconi anemia complementation group D1 | 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000045431 | SCV000494362 | benign | Hereditary breast ovarian cancer syndrome | 2014-04-03 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000120361 | SCV000538490 | uncertain significance | not specified | 2016-03-28 | 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: Clinvar: 10 labs classify as LB/Ben; ExAC: 0.2% (118/66734) European chromosomes |
Fulgent Genetics, |
RCV000083145 | SCV000575734 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-09-16 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000034461 | SCV000602845 | benign | not provided | 2023-10-18 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000129099 | SCV000683946 | likely benign | Hereditary cancer-predisposing syndrome | 2015-02-11 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000083145 | SCV000743343 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-08-24 | criteria provided, single submitter | clinical testing | |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000083145 | SCV000744534 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-09-21 | criteria provided, single submitter | clinical testing | |
Preventiongenetics, |
RCV000034461 | SCV000805774 | likely benign | not provided | 2017-03-21 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000083145 | SCV001139206 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000034461 | SCV002010316 | benign | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
National Health Laboratory Service, |
RCV000045431 | SCV002025842 | benign | Hereditary breast ovarian cancer syndrome | 2022-04-19 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000120361 | SCV002070556 | likely benign | not specified | 2021-09-22 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000129099 | SCV002531916 | benign | Hereditary cancer-predisposing syndrome | 2020-09-08 | criteria provided, single submitter | curation | |
Ce |
RCV000034461 | SCV002545114 | likely benign | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | BRCA2: BP1, BS3:Supporting, BS1 |
Center for Genomic Medicine, |
RCV000120361 | SCV002551768 | benign | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Biesecker Lab/Clinical Genomics Section, |
RCV000034461 | SCV000043228 | probably not pathogenic | not provided | 2012-07-13 | no assertion criteria provided | research | Converted during submission to Likely benign. |
ITMI | RCV000120361 | SCV000084513 | not provided | not specified | 2013-09-19 | no assertion provided | reference population | |
Sharing Clinical Reports Project |
RCV000083145 | SCV000115219 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2012-05-01 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000083145 | SCV000147282 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Pathway Genomics | RCV000083145 | SCV000207343 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-11-06 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001353905 | SCV000592175 | benign | Malignant tumor of breast | no assertion criteria provided | clinical testing | The p.Ala2717Ser variant has been identified in five individuals from our laboratory, 36 times in the UMD-BRCA2 database and 112 times in the BIC database. The variant was identified in 19 of 7810 proband chromosomes in individuals with breast, ovarian and prostate cancer patients (Edwards 2003, Diez 2003, Lubinski 2004, Salazar 2006, Giannini 2006, Soegaard 2008, Caux-Moncoutier 2009, Capanu 2011). However, an inadequate number of control chromosomes were tested to establish the variants frequency in the general population. This variant is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897747) and was identified in more than one population with an average heterozygosity of 0.004+/-0.046, increasing the likelihood that this is a low frequency benign variant. The Ala2717 residue is not highly conserved in mammals and neither computational analyses (SIFT, AlignGVGD) nor other in silico protein modeling predictions (Karchin 2008, Spurdle 2008) suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Finally, this variant was identified in at least three individuals in the UMD database who had a second premature truncating variant that is expected to be pathogenic, increasing the likelihood that the p.Ala2712Ser variant is not clinically significant. In summary, based on the above information this variant is classified as Benign. | |
Diagnostic Laboratory, |
RCV000083145 | SCV000733313 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | ||
Mayo Clinic Laboratories, |
RCV000034461 | SCV000778717 | benign | not provided | 2015-10-07 | no assertion criteria provided | clinical testing | |
True Health Diagnostics | RCV000129099 | SCV000787952 | likely benign | Hereditary cancer-predisposing syndrome | 2018-01-05 | no assertion criteria provided | clinical testing | |
Foulkes Cancer Genetics LDI, |
RCV000735609 | SCV000863747 | uncertain significance | Breast and/or ovarian cancer | 2001-02-15 | no assertion criteria provided | clinical testing | |
Laboratory of Diagnostic Genome Analysis, |
RCV000034461 | SCV001799396 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics Laboratory, |
RCV000120361 | SCV001906396 | benign | not specified | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000120361 | SCV001954450 | benign | not specified | no assertion criteria provided | clinical testing | ||
BRCAlab, |
RCV000083145 | SCV004243802 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2020-03-02 | no assertion criteria provided | clinical testing |