ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.964A>C (p.Lys322Gln) (rs11571640)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045881 SCV000073894 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000034472 SCV000108650 likely benign not provided 2020-02-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8840963, 25802882, 20104584, 23729402, 24884479, 26332594, 22703879, 21520273, 19016756, 21218378, 15168169, 27600092, 22771033, 28111427, 26692440, 29770616, 30415210, 29802286, 31131967)
Ambry Genetics RCV000131239 SCV000186196 benign Hereditary cancer-predisposing syndrome 2015-03-01 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 RCV000031841 SCV000220806 likely benign Breast-ovarian cancer, familial 2 2014-10-16 criteria provided, single submitter literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000031841 SCV000267232 uncertain significance Breast-ovarian cancer, familial 2 2016-03-18 criteria provided, single submitter reference population
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000414578 SCV000492490 uncertain significance Breast neoplasm criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074565 SCV000538478 likely benign not specified 2016-10-27 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 11 patients with breast cancer (7 of whom were Asian), 1 patient with hepatocellular carcinoma, and 1 patient with no history of cancer. It is present in ExAC with a Max MAF of 0.35%. At this frequency a pathogenic role is unlikely. It is classified as LB/B by 5 submitters in ClinVar with 1 star (Invitae, GeneDx, Ambry, Counsyl, SCRP) and as VUS by BIC and Biesecker lab.
Color Health, Inc RCV000131239 SCV000684083 likely benign Hereditary cancer-predisposing syndrome 2016-11-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034472 SCV000695260 likely benign not provided 2017-02-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.964A>C (p.Lys322Gln) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 30/123662 control chromosomes, predominantly in the East Asian cohort, 29/10878 (0.0027), which does exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Therefore, suggesting that the variant is a polymorphism found most frequently in population(s) of East Asian origin. In addition, the variant has been reported in 2 unaffected individuals (Carnery_2010), showing evidence for lack of co-segregation. Also multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Mendelics RCV000045881 SCV000838749 likely benign Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000031841 SCV001138983 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109314 SCV001266637 benign Fanconi anemia, complementation group D1 2017-04-30 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000031841 SCV001269209 benign Breast-ovarian cancer, familial 2 2017-04-30 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Research and Development, ARUP Laboratories RCV001642527 SCV001854657 likely 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034472 SCV000043193 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031841 SCV000054449 benign Breast-ovarian cancer, familial 2 2011-03-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031841 SCV000145797 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353591 SCV000591722 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Lys322Gln variant was identified in 7 of 5142 proband chromosomes from individuals with breast cancer, ovarian cancer, or hepatocellular carcinoma, and was absent in 88 control chromosomes (Borg 2010, Carney 2010, Katagiri 1996, Sugano 2008); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs11571640) “With unknown allele”, HGMD, and the BIC database (11X with unknown clinical importance). The variant was listed in 1000 Genomes Project with a frequency of 0.001, and the Japanese HapMap-JPT cohort with frequency of 0.006, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. This residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. One study predicted this variant to have no effect on cancer risk; however, this was limited to an in silico analysis (Capanu 2011). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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