Submissions for variant NM_000059.4(BRCA2):c.10082A>C (p.Gln3361Pro)

dbSNP: rs751250810

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001712440	SCV000564805	likely benign	not provided	2018-11-28	criteria provided, single submitter	clinical testing
Invitae	RCV000536779	SCV000635128	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570247	SCV000661456	likely benign	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000570247	SCV000903252	likely benign	Hereditary cancer-predisposing syndrome	2016-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797731	SCV002041794	uncertain significance	not specified	2021-11-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10082A>C (p.Gln3361Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 273876 control chromosomes in the gnomAD database and in one study surveying a control Han Chinese population (Dong_2021), including 1 homozygote in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.10082A>C has been reported in the literature in one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (Dorling_2021), however this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as Likely benign, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001712440	SCV002774482	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338602	SCV004048298	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	The missense variant c.10082A>C (p.Gln3361Pro) in BRCA2 gene has been submitted to ClinVar as a Variant of Uncertain Significance. The p.Gln3361Pro variant has been reported in the literature in one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (Dorling et al., 2021), however this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The p.Gln3361Pro variant is reported with the allele frequency (0.003%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Gln at position 3361 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Gln3361Pro in BRCA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357415	SCV001552882	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gln3361Pro variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs751250810) as "With Uncertain significance allele" and ClinVar (classified as likely benign by GeneDx; as uncertain significance by Invitae and Ambry Genetics). The variant was identified in control databases in 9 of 245868 chromosomes (1 homozygous) at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 9 of 30774 chromosomes (1 homozygous, freq: 0.0003); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gln3361 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,) 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. This variant is classified as a variant of uncertain significance.
BRCAlab, Lund University	RCV003338602	SCV004243890	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing