Submissions for variant NM_000465.4(BARD1):c.620A>G (p.Lys207Arg)

gnomAD frequency: 0.00218  dbSNP: rs34969857

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590348	SCV000149546	likely benign	not provided	2020-08-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30309722, 27742771, 28873162, 24123366, 26315354, 26976419, 25980754)
Ambry Genetics	RCV000115637	SCV000183941	likely benign	Hereditary cancer-predisposing syndrome	2018-06-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000199443	SCV000252710	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000199443	SCV000489170	likely benign	Familial cancer of breast	2016-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115637	SCV000682805	likely benign	Hereditary cancer-predisposing syndrome	2015-07-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200969	SCV000696779	benign	not specified	2019-02-19	criteria provided, single submitter	clinical testing	Variant summary: The variant, BARD1 c.620A>G (p.Lys207Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 263154 control chromosomes predominantly within the African subpopulation, at a frequency of 0.0072, in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. In addition, the variant was also reported in 47/2559 African American women (i.e. with a frequency of 0.018), who were older than 70 years of age, and never had cancer (in the FLOSSIES database); further supporting the benign nature of the variant. The variant, c.620A>G has been reported in the literature in an individual affected with ovarian cancer (Ramus 2015) and in three African American individuals affected with breast cancer (Tung 2015), however without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (1x)/likely benign (7x). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000590348	SCV000806133	likely benign	not provided	2017-03-09	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000200969	SCV000859725	likely benign	not specified	2018-02-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590348	SCV000887599	benign	not provided	2022-08-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115637	SCV002529634	likely benign	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000199443	SCV002801050	likely benign	Familial cancer of breast	2022-01-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000199443	SCV004016370	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000199443	SCV004019262	likely benign	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492482	SCV004240127	likely benign	Breast and/or ovarian cancer	2022-12-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200969	SCV004243123	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355275	SCV001550109	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Lys207Arg variant was identified in 3 of 10244 proband chromosomes (frequency: 0.0003) from individuals or families with stages I to III breast and or ovarian cancer, and Lynch Syndrome (Yurgelun_2015_25980754, Tung_2016_26976419, Ramus_2015_26315354). The variant was also identified in dbSNP (ID: rs34969857) as “With other allele”, and in ClinVar and Clinvitae (7x as benign by Invitae, likely benign by GeneDx, Ambry Genetics, Counsyl, Quest Diagnostics, Color Genomics, Laboratory Corporation of America). The variant was not identified in Cosmic, MutDB or the Zhejiang University Database. The variant was identified in control databases in 187 of 257912 chromosomes (1 homozygous) at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 166 of 23650 chromosomes (freq: 0.007), Other in 1 of 5942 chromosomes (freq: 0.00017), Latino in 15 of 29648 chromosomes (freq: 0.0005), European Non-Finnish in 5 of 120972 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Lys207Arg residue is not conserved in mammals and 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, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.