Submissions for variant NM_007294.4(BRCA1):c.1648A>C (p.Asn550His)

gnomAD frequency: 0.00029  dbSNP: rs56012641

Total submissions: 38

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031004	SCV000244306	benign	Breast-ovarian cancer, familial, susceptibility to, 1	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 = 0.00000000000163
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167815	SCV000075562	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000031004	SCV000154031	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-07	criteria provided, single submitter	literature only
GeneDx	RCV000168493	SCV000167243	benign	not specified	2014-01-22	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	RCV000162617	SCV000213049	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768647	SCV000219211	likely benign	Breast and/or ovarian cancer	2023-02-22	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031004	SCV000267693	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000168493	SCV000333421	likely benign	not specified	2015-08-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000031004	SCV000575710	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162617	SCV000682975	likely benign	Hereditary cancer-predisposing syndrome	2014-12-15	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000031004	SCV000746296	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656640	SCV000806899	likely benign	not provided	2017-05-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000031004	SCV001140598	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656640	SCV001151334	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BS3:Moderate, BS1
Illumina Laboratory Services, Illumina	RCV000031004	SCV001287420	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-11-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168493	SCV001337859	benign	not specified	2020-01-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1648A>C (p.Asn550His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 282970 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00026 vs 0.001), allowing no conclusion about variant significance. c.1648A>C has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Adem_2002, Guidugli_2011, Jalkh_2005, Augello_2006, Spurdle_2008, Solano_2013, Mahfoudh_2012, Wong-Brown_2015, Biunno_2014, Maresca_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 in our lab and other databases (BRCA1 c.5080G>T, p.Glu1694X; BRCA2 c.6082_6086delGAAGA, p.Glu2028LysfsX19; BRCA1 c.962G>A, p.Trp321Ter ; BRCA1 c.3544C>T, p.Gln1182Ter ; BRCA2 c.5682C>G, p.Tyr1894Ter ; BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. At least two publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Guidugli_2011, Maresca_2018). 13 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x), likely benign (7x) and benign (3x), including one expert panel (ENIGMA, benign). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000168493	SCV002070466	likely benign	not specified	2022-01-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162617	SCV002538044	benign	Hereditary cancer-predisposing syndrome	2020-06-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168493	SCV002551032	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656640	SCV002774135	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031004	SCV004016758	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656640	SCV004563111	benign	not provided	2023-09-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031004	SCV004818301	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656640	SCV005251074	benign	not provided		criteria provided, single submitter	not provided
Sharing Clinical Reports Project (SCRP)	RCV000031004	SCV000053597	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031004	SCV000144150	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	flagged submission	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148384	SCV000190082	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000167815	SCV000297223	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-09-02	flagged submission	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168493	SCV000538453	uncertain significance	not specified	2016-06-23	flagged submission	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 B/LB, including expert panel
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353786	SCV000591345	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asn550His variant has been identified in 8 of 1464 proband chromosomes (frequency 0.005) in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, El-Harith 2002 12070551, Jalkh 2012, Russo 2007, Solano 2012) and was absent in 200 control chromosomes from these studies. Myriad reports this variant as a polymorphism, and the Exome Server Project reports a frequency of 0.0003 in European American alleles, and 0.0002 in African American alleles. This variant has been also been reported in dbSNP (ID: rs56012641) “with non-pathogenic allele”, in the BIC database 54X as a variant of unknown clinical importance, and in UMD 19X as a neutral variant which co-occurred with a known pathogenic mutation, BRCA2 c.6082 6086delGAAGA (p.Glu2028LysfsX19), increasing the likelihood that the p.Asn550His variant does not have clinical significance. The p.Asn550 residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. Functional assays on the p. Asn550His variant have suggested that it has a neutral effect on BRCA1 function in homologous repair (Caligo 2008) and non-homologous end-joining (Guidugli 2011). Many studies have identified the p.Asn550His variant co-occurring with two other BRCA1 variants, p.Tyr179Cys and p.Phe486Lys, in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012), suggesting that together they constitute a rare haplotype (Tavtigian 2006). Furthermore, Augello (2006) identified these three mutations in three members of one family indicating that they exist in cis, and suggests that the presence of the three variants might produce an effect on the conformation of the protein and, consequently, on its function. 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	RCV000031004	SCV000733654	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656640	SCV000778767	likely benign	not provided	2017-08-02	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162617	SCV000805228	likely benign	Hereditary cancer-predisposing syndrome	2018-04-05	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168493	SCV001906112	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168493	SCV001957029	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000168493	SCV001970745	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168493	SCV002036899	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167815	SCV002506598	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-07	no assertion criteria provided	clinical testing