ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs80357271
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Total submissions: 11
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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) 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 2021-12-17 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,PreventionGenetics RCV000586665 SCV000806931 likely benign not provided 2017-01-10 criteria provided, single submitter clinical testing
Color Health, Inc 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.

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