ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1166C>A (p.Pro389Gln) (rs397507263)

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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) RCV000082883 SCV001161604 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 = 0.000287
Ambry Genetics RCV000129740 SCV000184546 likely benign Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing in silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000197010 SCV000252603 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000294429 SCV000383629 uncertain significance Fanconi anemia, complementation group D1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000082883 SCV000383630 likely benign Breast-ovarian cancer, familial 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx RCV000587492 SCV000515841 likely benign not provided 2020-11-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22752604, 26898890)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000436893 SCV000600469 likely benign not specified 2017-05-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587492 SCV000694513 benign not provided 2016-06-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1166C>A (p.Pro389Gln) variant involves the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain and 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 60/120896 control chromosomes (2 homozygotes), predominantly observed in the South Asians, a frequency of 0.0036399 (60/16484). This subpopulation frequency is about 5 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been cited in 2 breast cancer patients without evidence of causality (i.e. co-segregation). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign. Taken together and based on the high allele frequency in the South Asian subpopulation in the ExAC database, this missense variant is classified as Benign.
3DMed Clinical Laboratory Inc RCV000677855 SCV000804015 uncertain significance Breast neoplasm 2017-06-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587492 SCV000887749 benign not provided 2018-06-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129740 SCV000910641 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001647069 SCV001854668 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) RCV000082883 SCV000114957 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353634 SCV000591731 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Pro389Gln variant was identified in 3 of 674 proband chromosomes (frequency: 0.005) from individuals or families with breast or ovarian cancer and was not identified in 100 control chromosomes from healthy individuals (Caminsky 2016, Juwle 2012). The variant was also identified in dbSNP (ID: rs397507263) as "With other allele", ClinVar (classified as benign by Invitae and SCRP; as likely benign by six submitters; and as uncertain significance by one submitter), COGR, and UMD-LSDB (1x as unclassified variant). The variant was not identified in Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or the Zhejiang University database. The variant was identified in control databases in 103 of 245960 chromosomes (3 homozygous) at a frequency of 0.0004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 100 of 30696 chromosomes (freq: 0.003) and Other in 3 of 5476 chromosomes (freq: 0.0006), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Pro389 residue is conserved in mammals but not in more distantly related organisms. However, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and four out of five 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, this variant meets our laboratory's criteria to be classified as benign.

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