Submissions for variant NM_007294.4(BRCA1):c.3130A>G (p.Ile1044Val)

gnomAD frequency: 0.00002  dbSNP: rs80357271

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031091	SCV000244335	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 = 0.00000234
Invitae	RCV001086298	SCV000076090	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000048077	SCV000209949	likely benign	not specified	2017-12-27	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	RCV000162795	SCV000213273	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.
Counsyl	RCV000031091	SCV000489433	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586665	SCV000699004	likely benign	not provided	2016-11-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3130A>G (p.Ile1044Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/121366 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Multiple studies (Easton_BRCA2_AJHG_2007, Lindor_BRCA2_HM_2012, Pavlicek_HMG_2004, et al.), using different analyses such as comparative sequence comparison and computational multifactorial probability based modeling classified variant of interest as benign. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. There is an internal specimen carrying this variant also carries a deleterious BRCA2 variant. Therefore, taken together, this variant has been classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000586665	SCV000806931	likely benign	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162795	SCV000902950	benign	Hereditary cancer-predisposing syndrome	2017-03-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031091	SCV000053687	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-07-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031091	SCV000144646	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	RCV001353907	SCV000591428	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Ile1044Val variant was identified in the literature in a large data set of probands tested by Myriad Genetic Laboratories; however, the number of probands positive for the variant was not indicated (Easton 2007). The variant was identified in dbSNP (ID: rs80357271), LOVD, the BIC database (1X with unknown clinical importance, and Clinvar (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports). The c.3130A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 4 of 5 different programs. The p.Ile1044 residue is not conserved in mammals and the variant amino acid valine (Val) is present in dog, cow, and chicken, 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. However, this information is not predictive enough to rule out pathogenicity. Two multifactorial likelihood-ratio models predict the variant to be neutral or not pathogenic (Easton 2007, Lindor 2012). 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.