ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4928T>C (p.Val1643Ala) (rs28897731)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044524 SCV000072537 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000160187 SCV000210531 likely benign not specified 2017-10-17 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 RCV000163029 SCV000213517 likely benign Hereditary cancer-predisposing syndrome 2019-01-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Michigan Medical Genetics Laboratories,University of Michigan RCV000077341 SCV000267773 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416148 SCV000493200 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163029 SCV000910874 benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Mendelics RCV000077341 SCV001139097 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000416148 SCV001469436 uncertain significance not provided 2019-09-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077341 SCV000109138 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077341 SCV000146507 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044524 SCV000586956 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353540 SCV000591932 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val1643Ala variant was identified in 1 of 698 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was found not to segregate with disease in the proband’s two family members with breast cancer (Fernandes 2016). The variant was also identified in dbSNP (ID: rs28897731) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by GeneDx, Ambry Genetics, Invitae, and Michigan Medical Genetics; and as uncertain significance by Humangenetik Teubingen, COGR, and BIC), and LOVD 3.0 (classified as uncertain or NA by 3 submitters). The variant has been identified by our laboratory in at least three individuals with breast cancer; one of whom also has a co-occurring pathogenic ATM variant (c.5712dup, p.Ser1905Ilefs*25). The variant was identified in control databases in 7 of 239572 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 32346 chromosomes (freq: 0.00003), European in 3 of 109484 chromosomes (freq: 0.00003), and South Asian in 3 of 28946 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Val1643 residue is not conserved in mammals and 5 of 5 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) 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.