ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5333A>G (p.Asp1778Gly) (rs80357041)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081585 SCV000076958 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129616 SCV000184409 benign Hereditary cancer-predisposing syndrome 2014-12-08 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.
GeneDx RCV000048945 SCV000209990 likely benign not specified 2017-09-15 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589573 SCV000600418 likely benign not provided 2019-06-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129616 SCV000683298 likely benign Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589573 SCV000699243 likely benign not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5333A>G (p.Asp1778Gly) variant located in the BRCT domain on the surface of the structure and distant from the phosphopeptide binding site (UniProt, Gaboriau_2015) involves the alteration of a conserved nucleotide at the start of exon 21 and is predicted to be damaging by 3/4 in silico (SNPs&GO not captured due to low reliability index). Due to its location, the variant is predicted to have a role in splicing; however 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of an ESE site. Multiple functional studies (in vitro minigene as well as mRNA analysis) show that it has no effect in splicing (Thomassen_2011, Colombo_2013, Ahlborn_2015). In addition, the variant has no effect on homology-directed recombination (HDR), protein folding, phosphopeptide binding and transcription (Lee_2010, Lu_2015). This variant was found in 1/120994 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple HBOC patients/families or in individuals undergoing BRCA1/2 testing. In one reported family, while this variant was found in the proband, it was not found in the affected mother, suggesting a possible lack of cosegregation evidence against pathogenicity (Colombo_2013). In ClinVar, while three labs classify it as benign/likely benign, two labs classify it as uncertain significance. Taken together, this variant is currently classified as Likely Benign.
Counsyl RCV000077617 SCV000785002 likely benign Breast-ovarian cancer, familial 1 2017-03-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077617 SCV000109420 benign Breast-ovarian cancer, familial 1 2010-07-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077617 SCV000145467 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353416 SCV000591616 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp1778Gly variant was identified in 2 of 266 proband chromosomes (frequency 0.008) from individuals with breast cancer (Thomassen 2012, Tommasi 2005), and was also reported by our lab in an Italian individual with breast cancer. The variant was identified in dbSNP (ID: rs80357041) “With unknown allele” but no frequency information was provided, so the prevalence of this variant in the general population is not known. The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was also reported in HGMD, LOVD, once in the UMD as an unclassified variant, and once in the BIC database with unknown clinical importance. The p.Asp1778Gly variant occurs in the first base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing; however, in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) yielded inconsistent predictions of this variant on splicing and this information is not very predictive of pathogenicity. Two studies using RT-PCR analysis of the variant found no aberrant changes to the BRCA1 mRNA transcript, indicating that this variant exhibits normal splicing (Colombo 2012, Thomassen 2012). The p.Asp1778 residue is conserved in mammals but not in lower organisms, with the variant amino acid Glycine (Gly) present in chicken, increasing the likelihood that this variant may not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The results of studies assessing the impact of the variant on the protein are conflicting: a study by Mirkovic (2004) using in silico protein structure modeling predicts this variant to be deleterious; however, algorithms developed by Karchin (2007) predict this variant to be neutral, and a functional study by Lee (2010) found no effect of this variant on BRCA1 protein stability, protein binding and transcriptional activity. 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 predicted benign.
Brotman Baty Institute,University of Washington RCV000077617 SCV001238193 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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