Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001085159 | SCV000072866 | benign | Hereditary breast ovarian cancer syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000166682 | SCV000217490 | benign | Hereditary cancer-predisposing syndrome | 2015-08-15 | 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. |
CHEO Genetics Diagnostic Laboratory, |
RCV000768600 | SCV000324853 | uncertain significance | Breast and/or ovarian cancer | 2015-12-11 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000586884 | SCV000512377 | likely benign | not provided | 2020-04-06 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 22713736, 19619314, 16949048, 12955716, 29061375, 14517958, 12624724) |
Color Diagnostics, |
RCV000166682 | SCV000683755 | likely benign | Hereditary cancer-predisposing syndrome | 2017-05-11 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000431388 | SCV000694942 | likely benign | not specified | 2023-11-24 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.6131G>C (p.Gly2044Ala) 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 3.1e-05 in 358056 control chromosomes (gnomAD, Diez_2003, Dorling_2021). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.6131G>C has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence of causality (Diez_2003, Martinez-Ferrandis_2003, Palomba_2009, Jalkh_2012, Santonocito_2020, Foglietta_2020, Patruno_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.5984dup, p.Asn1995LysfsX8; BRCA2 c.5980C>T, p.Gln1994Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22713736, 12955716, 19619314, 14517958, 32438681, 33471991, 32806537, 34572941). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=2), likely benign (n=6), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000586884 | SCV000887865 | likely benign | not provided | 2023-08-02 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001330945 | SCV001522805 | uncertain significance | Fanconi anemia complementation group D1 | 2020-05-05 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
ARUP Laboratories, |
RCV000586884 | SCV002049101 | likely benign | not provided | 2021-01-20 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000166682 | SCV002536205 | likely benign | Hereditary cancer-predisposing syndrome | 2020-11-11 | criteria provided, single submitter | curation | |
University of Washington Department of Laboratory Medicine, |
RCV000166682 | SCV003850964 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
Sharing Clinical Reports Project |
RCV000031601 | SCV000054208 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2010-04-22 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000031601 | SCV000146775 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2004-02-20 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001353819 | SCV000592031 | likely benign | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA2 p.Gly2044Ala variant was identified in 5 of 2336 proband chromosomes (frequency: 0.003) from Spanish, Lebanese and Sardinian (Italian) individuals or families with sporadic breast cancer, early onset breast cancer and/or HBOC and was not identified in 606 control chromosomes from healthy individuals (Palomba 2009 , Martinez-Ferrandis 2003, Jalkh 2012, Diez 2003). In 1 proband, the variant was found to co-occur with a truncating BRCA2 mutation (p.Q1994X) and hence determined to be a rare polymorphism because it altered a non-conservative residue and was absent in controls (Martinez-Ferrandis 2003). The variant was also identified in dbSNP (ID: rs56191579) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity: classified benign by Ambry Genetics and SCRP (Sharing Clinical Reports Project); likely benign by GeneDx and Invitae; and uncertain significance by CHEO Genetics Diagnostic Lab, Quest Diagnostics Nichols Institute San Juan Capistrano and BIC), Clinvitae (4X), UMD-LSDB (3x as 3-UV), and BIC Database (3x clinical importance unknown, classification pending). The variant was not identified in COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 1 individual with breast cancer and in control databases in 6 of 245748 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15274 chromosomes (freq: 0.00007), Other in 1 of 5472 chromosomes (freq: 0.0002), Latino in 1 of 33566 chromosomes (freq: 0.00003), European Non-Finnish in 3 of 111442 chromosomes (freq: 0.00003), and not in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gly2044 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. | |
Laboratory of Diagnostic Genome Analysis, |
RCV000586884 | SCV002035597 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000586884 | SCV002038191 | likely benign | not provided | no assertion criteria provided | clinical testing |