ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2803G>C (p.Asp935His) (rs28897716)

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Total submissions: 14
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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) RCV000113094 SCV001161612 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 = 0.000816
Invitae RCV001082675 SCV000072075 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131164 SCV000186109 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.
GeneDx RCV000586933 SCV000278841 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2803G>C at the cDNA level, p.Asp935His (D935H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant, also known as BRCA2 3031G>C using alternate nomenclature, has been observed in several individuals with a personal or family history of breast cancer, one individual with pancreatic cancer, and one individual with prostate cancer (Edwards 2003, Vogel 2007, Haffty 2009, Caux-Moncoutier 2011, Becker 2012, Hu 2015). BRCA2 Asp935His was observed at an allele frequency of 0.009% (6/66390) in individuals of European (non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp935His occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Asp935His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113094 SCV000487999 uncertain significance Breast-ovarian cancer, familial 2 2015-12-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001002667 SCV000694630 likely benign not specified 2020-12-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2803G>C (p.Asp935His) 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 6.4e-05 in 250844 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.2803G>C has been reported in the literature in individuals affected with familial breast/ovarian cancer (example, Vogel_2007, Lee_2008, Caux-Moncoutier_2011, Haffty_2009), prostate cancer (example, Edwards_2003), pancreatic cancer (example, Hu_2015), unrelated presentations such as schizophrenia or schizoaffective disorder (example, Need_2012) as well unaffected individuals (example, Becker_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on double stranded break repair capacity as measured by levels of chromosomal damage upon irradiation (example, Becker_2012). "A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (CAGI class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). "Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Since its previous evaluation, at-least three submitters, to include the expert panel have settled upon a classification as likely benign (n=2)/benign (n=1, expert panel). The expert panel assessment is supported by a large scale multifactorial likelihood analysis reporting a benign outcome (Parsons_2019). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome as outlined above, the variant was re-classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586933 SCV000889010 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131164 SCV000902829 likely benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Mendelics RCV000113094 SCV001139043 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002667 SCV001160655 uncertain significance not specified 2019-06-27 criteria provided, single submitter clinical testing The BRCA2 c.2803G>C; p.Asp935His variant (rs28897716), is reported in the literature in individuals with breast and/or ovarian cancer (Caux-Moncoutier 2011, Haffty 2009, Vogel 2007) and in individuals with prostate cancer (Edwards 2003). This variant is reported in ClinVar but with conflicting interpretations (Variation ID: 37801). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (16/250844 alleles) in the Genome Aggregation Database. The aspartate at codon 935 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this BRCA2 variant is uncertain at this time. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34. Edwards SM et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003 Jan; 72 (1):1-12. Haffty BG et al. Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and rish of secondary malignancies across diverse racial groups. Ann Oncol. 2009 Oct; 20(10):1653-9. Vogel KJ et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol. 2007 Oct 10; 25(29):4635-41.
Illumina Clinical Services Laboratory,Illumina RCV000113094 SCV001269414 uncertain significance Breast-ovarian cancer, familial 2 2018-01-25 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001111815 SCV001269415 uncertain significance Fanconi anemia, complementation group D1 2018-01-25 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170459 SCV001333039 uncertain significance Breast and/or ovarian cancer 2018-05-30 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113094 SCV000146114 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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