Submissions for variant NM_000059.4(BRCA2):c.1810A>G (p.Lys604Glu)

gnomAD frequency: 0.00001  dbSNP: rs80358467

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031341	SCV001161608	benign	Breast-ovarian cancer, familial, susceptibility to, 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 = 0.000415
Ambry Genetics	RCV000129177	SCV000183912	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: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084993	SCV000283176	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000031341	SCV000488958	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000425351	SCV000512342	likely benign	not specified	2017-12-21	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000425351	SCV000694569	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1810A>G (p.Lys604Glu) results in a 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. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (CAGI class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant allele was found at a frequency of 2.9e-05 in 240642 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1810A>G has been reported in the literature in individuals affected with Breast And Ovarian Cancer (example, Ritterhouse_2016, Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the UMD database and observed at our laboratory (UMD - BRCA1 c.5263_5264insC, p.Ser1755?fs; Our laboratory - BRCA1 c.68_69delAG, p.Glu23ValfsX17), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The variant is classified predominantly as benign (Expert Panel)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000129177	SCV000902945	benign	Hereditary cancer-predisposing syndrome	2016-11-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590202	SCV001133695	likely benign	not provided	2019-03-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129177	SCV002533265	likely benign	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004803007	SCV004846975	benign	BRCA2-related cancer predisposition	2024-08-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031341	SCV000053946	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-11-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031341	SCV000145947	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353814	SCV000591771	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Lys604Glu variant has not been previously reported in the literature, though it has been recorded in the BIC (x9) database. It is listed in the dbSNP database as coming from a "clinical source" (ID#:rs80358467), but no frequency information was provided, and so the prevalence of this variant in the population is not known. This residue is conserved in mammals, and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. 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.
Department of Medical and Surgical Sciences, University of Bologna	RCV000031341	SCV004228379	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)