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

gnomAD frequency: 0.00001  dbSNP: rs80357041

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081585	SCV000076958	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	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	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	RCV000048945	SCV000699243	benign	not specified	2021-11-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5333A>G (p.Asp1778Gly) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function and 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5333A>G has been reported in the literature in individuals affected with Breast And Ovarian Cancer (Judkins_2005, Thomassen_2011, Colombo_2013, Tommasi_2005, Santonocito_2020, Dorling_2021). In families with this variant, 2 transmissions of the variant allele and 1 transmissions of the reference allele to affected individuals was reported (Colombo_2013, Santonocito_2013), however in one reported family this variant was found in the proband but not found in the affected mother, suggesting a possible lack of cosegregation which is evidence against pathogenicity (Colombo_2013). In a recent case-control study, the results showed that this variant does not associate with breast cancer (Dorling_2021). At least eight publications report experimental evidence evaluating an impact on protein function and showed no damaging effect of this 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.
Counsyl	RCV000077617	SCV000785002	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-03-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077617	SCV002030101	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000129616	SCV002537843	likely benign	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003894901	SCV004708944	likely benign	BRCA1-related condition	2024-01-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000077617	SCV000109420	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-07-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077617	SCV000145467	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 1		no assertion provided	in vitro