Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.3130A>G(p.Ile1044Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1044M) has been classified as Likely benign.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.041401654).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43092401-T-C is Benign according to our data. Variant chr17-43092401-T-C is described in ClinVar as [Benign]. Clinvar id is 37510.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092401-T-C is described in Lovd as [Benign].
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:3
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Feb 20, 2004
- -
Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Jul 29, 2008
- -
Benign, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Aug 10, 2015
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 -
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Oct 11, 2016
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not provided Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Nov 07, 2016
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. -
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Jan 10, 2017
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Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 18, 2014
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -
Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Mar 31, 2017
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not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Dec 27, 2017
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. -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
-
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. -
Hereditary breast ovarian cancer syndrome Benign:1