ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1648A>C (p.Asn550His) (rs56012641)

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Total submissions: 28
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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 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
Invitae RCV000167815 SCV000075562 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000031004 SCV000154031 likely benign Breast-ovarian cancer, familial 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: 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 2016-06-16 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031004 SCV000267693 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000167815 SCV000297223 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-09-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000168493 SCV000333421 likely benign not specified 2015-08-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168493 SCV000538453 uncertain significance not specified 2016-06-23 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 B/LB, including expert panel
Fulgent Genetics,Fulgent Genetics RCV000031004 SCV000575710 likely benign Breast-ovarian cancer, familial 1 2015-09-01 criteria provided, single submitter clinical testing
Color Health, Inc 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 1 2020-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656640 SCV000806899 likely benign not provided 2017-05-16 criteria provided, single submitter clinical testing
Mendelics RCV000031004 SCV001140598 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656640 SCV001151334 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031004 SCV001287420 benign Breast-ovarian cancer, familial 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.
Research and Development, ARUP Laboratories RCV001659753 SCV001878198 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031004 SCV000053597 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031004 SCV000144150 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148384 SCV000190082 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
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 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
Human Genetics - Radboudumc,Radboudumc RCV000168493 SCV001957029 benign not specified no assertion criteria provided clinical testing

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