Submissions for variant NM_000059.4(BRCA2):c.5312G>A (p.Gly1771Asp)

gnomAD frequency: 0.00021  dbSNP: rs80358755

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031539	SCV000244456	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.000000153
Invitae	RCV000044634	SCV000072647	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000031539	SCV000154060	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000168575	SCV000167372	benign	not specified	2014-03-06	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.
Ambry Genetics	RCV000162664	SCV000213106	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768599	SCV000219350	likely benign	Breast and/or ovarian cancer	2023-04-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031539	SCV000383714	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044634	SCV000494421	benign	Hereditary breast ovarian cancer syndrome	2015-04-09	criteria provided, single submitter	clinical testing	Variant Summary: The variant of interst causes a missense change in a non-conserved position with 3/5 in silico programs predicting a "benign" outcome. The variant of interest has an observed allele frequency of 41/121940 (1/2976) including 1 homozygous occurrence. Functional analysis through the use of allelic imbalance implicated the variant does not affect splicing (Caux-Moncoutier_2009). The variant of interest has been reported in multiple affected individuals, however, it has shown lack of co-segregation within one family with an affected individual not carrying the variant of interest (Carvallone_2010). In addition, the variant of interest was reported to co-occur with another potentially pathogenic BRCA2 variant, c.759_759delinsACA and a potentially pathogenic BRCA1 variant, c.212+3A>G. Furthermore, multiple reputable databases/laboratories (ARUP, UMD, SCRP, GeneDx and Ambry Genetics) and publications (Lindor_2012, Easton_2007, and Cunningham_2014) classify the variant as "likely benign/benign/polymorphism." Therefore, taken all together, the variant of interest is classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168575	SCV000538487	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: 7 labs classify as LB/Ben; ExAC: 0.1% (6/11554) Latino chromosomes
Fulgent Genetics, Fulgent Genetics	RCV000031539	SCV000575746	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-08	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000168575	SCV000588100	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168575	SCV000602747	benign	not specified	2018-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162664	SCV000683694	likely benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031539	SCV000743306	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031539	SCV000744467	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034445	SCV000805720	likely benign	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000031539	SCV001139112	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001028067	SCV001270127	uncertain significance	Fanconi anemia complementation group D1	2018-03-06	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.
Genetic Services Laboratory, University of Chicago	RCV000168575	SCV002070522	likely benign	not specified	2019-07-29	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044634	SCV002504853	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044634	SCV002515118	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162664	SCV002536125	benign	Hereditary cancer-predisposing syndrome	2020-09-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168575	SCV002550347	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044634	SCV004014964	benign	Hereditary breast ovarian cancer syndrome	2023-04-11	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031539	SCV004016827	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034445	SCV004132987	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS3:Supporting, BS1
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034445	SCV000043212	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031539	SCV000054144	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2006-03-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031539	SCV000146599	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168575	SCV000591959	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Gly1771Asp variant was identified in 6 of 1934 proband chromosomes from individuals with breast cancer, ovarian cancer or prostate cancer and was not detected in 100 control chromosomes evaluated (Edwards 2003, Hadjisavvas 2003, Hondow 2011, Kauff 2002, Thirthagiri 2008, Toh 2008). The variant was listed in dbSNP (ID: rs80358755) “With probable-non-pathogenic allele” with a minor allele frequency of 0.0005 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project (with a frequency of 0.0006 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, LOVD, the BIC database (43X with no clinical importance, 1X with unknown clinical importance), and in UMD (25X as a neutral variant). In UMD the variant was twice listed co-occur with a pathogenic variant in BRCA1 or BRCA2 (BRCA2 c.759 759delinsACA (p.Ser253ArgfsX24) and BRCA1 c.IVS5+3A>G (c.212+3A>G)), increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein (though this information is not predictive enough to rule out pathogenicity), and two in silico studies using multifactorial likelihood-ratio models predict the variant to be neutral or of no clinical significance (Easton 2007, Lindor 2012). Furthermore, the p.Gly1771 residue is not conserved in mammals and lower organisms, and the variant amino acid aspartic acid (Asp) is present in rat and mouse, further increasing the likelihood that this variant is not clinically important. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031539	SCV000733266	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001028067	SCV001190846	benign	Fanconi anemia complementation group D1	2020-02-05	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168575	SCV001952004	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168575	SCV002034335	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168575	SCV002036522	benign	not specified		no assertion criteria provided	clinical testing