ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6325G>A (p.Val2109Ile) (rs79456940)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195307 SCV000072926 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129753 SCV000184560 likely benign Hereditary cancer-predisposing syndrome 2018-12-04 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000034454 SCV000210386 likely benign not provided 2020-03-02 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 11595708, 19491284, 26709275, 27907908, 31131967, 30415210, 15117986, 14647438, 19016756, 27376475, 27124784, 22995991, 18779604, 15168169, 27658390, 28222693, 27997549, 27701467, 29215753, 28111427, 14973102, 28392550, 30725392, 29642553, 31825140, 22703879)
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240685 SCV000265952 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000406166 SCV000383740 likely benign Fanconi anemia, complementation group D1 2019-03-19 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.
Illumina Clinical Services Laboratory,Illumina RCV000113573 SCV000383741 likely benign Breast-ovarian cancer, familial 2 2019-03-19 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034454 SCV000609564 likely benign not provided 2017-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034454 SCV000694965 likely benign not provided 2016-12-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6325G>A (p.Val2109Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 38/122036 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0038354 (33/8604). This frequency is about 5 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature, mostly of Asian origin, without strong evidence for causality. BIC reports the variant in 2 individuals who also carry pathogenic variants (BRCA1 c.4163_4164insA; BRCA2 c.9076C>T), also supportive of a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, although some classify it as a VUS. Taken together, this variant is classified likley benign.
Counsyl RCV000113573 SCV000784864 likely benign Breast-ovarian cancer, familial 2 2017-01-18 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677821 SCV000803981 uncertain significance Cancer of the pancreas 2018-05-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129753 SCV000902701 likely benign Hereditary cancer-predisposing syndrome 2015-11-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034454 SCV001502166 uncertain significance not provided 2021-01-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034454 SCV000043221 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113573 SCV000146827 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113573 SCV000297542 benign Breast-ovarian cancer, familial 2 2008-10-28 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353658 SCV000592044 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val2109Ile variant was identified in 7 of 1460 proband chromosomes from Asian individuals with breast or ovarian cancer, and was absent in 520 control chromosomes from healthy individuals (Choi 2004, Haffty 2009, Hu 2004, Kawahara 2004, Sekine 2001, Sugano 2008). The variant was also identified in HGMD, UMD (1X as an unclassified variant), and the BIC database (8X with unknown clinical importance). The variant is listed in dbSNP (ID: rs79456940) “With unknown allele”, with a minor allele frequency of 0.0005 from the 1000 Genomes project, though this frequency is based on only one occurrence of the variant in the tested cohort. The p.Val2109 residue is not conserved in mammals and lower organisms, and the variant amino acid isoleucine (Ile) is present in dog, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein, and Myriad classifies this as a polymorphism (personal communication). In addition, this variant was identified by our laboratory in one individual with a co-occurring pathogenic variant, further increasing the likelihood that this variant may not have clinical importance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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