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

Total submissions: 13

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	2019-12-31	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	RCV000436893	SCV000515841	likely benign	not specified	2017-06-02	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.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000436893	SCV000591731	likely benign	not specified	2015-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000436893	SCV000600469	likely benign	not specified	2017-05-24	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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
Sharing Clinical Reports Project (SCRP)	RCV000082883	SCV000114957	benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing