ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3022A>G (p.Met1008Val) (rs56321129)

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Total submissions: 12
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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) RCV000111984 SCV000244330 benign Breast-ovarian cancer, familial 1 2015-08-10 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 = 0.00000000000204
Invitae RCV000167781 SCV000076063 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000120275 SCV000167286 benign not specified 2014-04-08 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.
CSER _CC_NCGL, University of Washington RCV000148396 SCV000190095 uncertain significance Malignant tumor of prostate 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Ambry Genetics RCV000162756 SCV000213232 benign Hereditary cancer-predisposing syndrome 2014-11-18 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120275 SCV000224984 likely benign not specified 2014-12-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162756 SCV000910720 benign Hereditary cancer-predisposing syndrome 2015-10-28 criteria provided, single submitter clinical testing
Mendelics RCV000111984 SCV001140565 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120275 SCV001156829 likely benign not specified 2018-08-29 criteria provided, single submitter clinical testing
ITMI RCV000120275 SCV000084427 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111984 SCV000144612 benign Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353548 SCV000591419 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Met1008Val variant was identified in 12 of 114808 proband chromosomes (frequency: 0.0001) from individuals or families with breast, ovarian and prostate cancer (Bodian 2014, Dorschner 2013, Judkins 2005, Zuhlke 2004). The variant was also identified in dbSNP (ID: rs56321129) “With untested allele”, with a minor allele frequency of 0.0004 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, the ClinVar database (classified as a bening variant) the BIC database (17X with no clinical importance), and UMD (6X as a neutral variant). The variant was identified by the Exome Variant Server project in 10 of 4406 African American alleles (frequency: 0.002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Met1008 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 p.Met1008 variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Two studies classified the variant as VUS (Dorschner 2013, Judkins 2005). Studies by Abkevich (2004) and Lindor (2012) identified this variant as likely to be neutral or of little clinical significance. Furthermore, functional studies (Judkins 2005, Tavtigian 2006) observed the variant in trans with known deleterious mutations and stated that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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