ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.956A>C (p.Asn319Thr) (rs55939572)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083417 SCV000073868 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000045855 SCV000210552 benign not specified 2014-07-21 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 RCV000162692 SCV000213146 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.
Counsyl RCV000031831 SCV000220311 likely benign Breast-ovarian cancer, familial 2 2014-05-13 criteria provided, single submitter literature only
Genetic Services Laboratory, University of Chicago RCV000045855 SCV000593700 likely benign not specified 2016-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162692 SCV000684073 likely benign Hereditary cancer-predisposing syndrome 2015-08-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000045855 SCV000805796 benign not specified 2017-06-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758980 SCV000887970 benign not provided 2018-05-22 criteria provided, single submitter clinical testing
Mendelics RCV000031831 SCV001138982 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031831 SCV001266633 likely benign Breast-ovarian cancer, familial 2 2019-02-25 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001109312 SCV001266634 uncertain significance Fanconi anemia, complementation group D1 2019-02-25 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286110 SCV001472636 likely benign none provided 2019-10-25 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642521 SCV001854655 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031831 SCV000054439 benign Breast-ovarian cancer, familial 2 2008-09-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031831 SCV000145792 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735629 SCV000863767 uncertain significance Breast and/or ovarian cancer 2001-12-28 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357124 SCV001552483 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asn319Thr variant was identified in 1 of 200 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Peixoto 2006). The variant was also identified in dbSNP (ID: rs55939572) as "With other allele ", ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, SCRP; as likely benign by Counsyl, Color Genomics, Genetic Services Laboratory, University of Chicago; as uncertain significance by BIC), COGR (3x a Likely Benign/Benign), LOVD 3.0 (6x), UMD-LSDB (9x as likely neutral), BIC Database (10x with unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in Cosmic, MutDB, and Zhejiang University databases. The variant was identified in control databases in 31 of 225112 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 4 of 4876 chromosomes (freq: 0.001), Latino in 21 of 28194 chromosomes (freq: 0.001), European in 6 of 105630 chromosomes (freq: 0.0001); but not in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Functional assay using multifactorial likelihood ratio model showed the variant displayed combined odds in favor of neutrality of 50:1, displayed substantial increases in homology-directed recombination repair activity and maintained the background level of centriole and centrosome amplification found in wild-type cells (Farrugia 2008). The p.Asn319 residue is not conserved in mammals and four out of five 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.

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