Submissions for variant NM_007294.4(BRCA1):c.2522G>A (p.Arg841Gln)

gnomAD frequency: 0.00006  dbSNP: rs80357337

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083060	SCV000075881	benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132442	SCV000187536	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
GeneDx	RCV001703950	SCV000209940	likely benign	not provided	2021-05-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20104584, 23867111, 15385441, 18273839, 21520273, 11400546, 8968716, 16267036, 23893897, 19370767, 33087888)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047868	SCV000698964	benign	not specified	2019-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2522G>A (p.Arg841Gln) 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 4.2e-05 in 283280 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.2e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.2522G>A, has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Barker_1996, Borg_2010, Judkins_2005, Schoumacher_2001, Brianese_2018, Zuntini_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2126insA, [p.Phe709TyrfsX3; BRCA2 c.7069_7070delCT , p.Leu2357ValfsX2; BRCA1 c.5152+2T>G), providing supporting evidence for a benign role. Additionally, one publication reports the variant present in a breast cancer patient, but absent in her affected mother, while both patients had a different pathogenic BRCA1 mutation, suggesting lack of segregation of the variant with disease (Zuntini_2018). Two publications have conducted functional studies: one used minigene splicing assays (Anczukow_2008) and one used functional complementation assays in cultured mouse embryonic stem cells (Bouwman_2013), both of which showed no significant effect on function caused by the variant. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083185	SCV000743414	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000083185	SCV000744654	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132442	SCV000902867	benign	Hereditary cancer-predisposing syndrome	2015-11-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132442	SCV002538133	benign	Hereditary cancer-predisposing syndrome	2021-07-04	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001703950	SCV004009796	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BP4, BS3:Moderate
Sharing Clinical Reports Project (SCRP)	RCV000083185	SCV000115259	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083185	SCV000144467	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353648	SCV000591393	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg841Gln variant was identified in 2 of 4282 proband chromosomes (frequency: 0.0004) from individuals or families with hereditary breast and ovarian cancer (Borg 2010, Schoumacher 2001). The variant was also identified in dbSNP (ID: rs80357337) “With other allele”, Exome Aggregation Consortium (ExAC) database, HGMD 3X, the ClinVar database 5X with conflicting classifications (classified as benign (SCRP and Ambry Genetics), likely benign (GeneDx), and uncertain significance (BIC - 6X); UMD reported the variant (10X as a likely neutral variant) and the Exome Aggregation Consortium (ExAC) database in 5 of 66708 (European (Non-Finnish)) alleles (frequency: 0.00007495), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. In UMD the variant was identified with two co-occurring pathogenic variants, a BRCA1 variant p.Phe709TyrfsX3, and a BRCA2 variant p.Leu2357ValfsX2 increasing the likelihood that the p.Arg841Gln variant does not have clinical significance. The p.Arg841 residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in orangutans, macaques, mice, dogs, cows, frogs and sea urchins, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In addition, functional studies based on the physiologic expression of the full length BRCA1 cDNA in mice (Bouwman 2013) and in silico studies (Capanu 2011) showed the variant to be neutral. One in 5 splicing software suggested that this variant may create an alternative 3' splice site (human splicing finder), but this information is not very predictive of pathogenicity. Lastly, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, the clinical significance of this variant could not be determined with absolute certainty although we would lean towards a more benign role for this variant. This variant meets our laboratory's criteria to be classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001703950	SCV001906341	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001703950	SCV001952446	likely benign	not provided		no assertion criteria provided	clinical testing