Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.4941C>A(p.Asn1647Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1268673).
BP6
Variant 17-43070973-G-T is Benign according to our data. Variant chr17-43070973-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Nov 30, 1998
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Hereditary cancer-predisposing syndrome Benign:2
Oct 10, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jan 18, 2019
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This alteration is classified as likely 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. -
not provided Uncertain:1
Feb 26, 2014
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.4941C>A at the cDNA level, p.Asn1647Lys (N1647K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAA). This variant was found in one study to have no protein folding defect, normal peptide binding activity and specificity, and normal trascriptional activity (Lee 2010). BRCA1 Asn1647Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is only moderately conserved throughout evolution and is located in BRCT1 domain (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRCA1 Asn1647Lys to be a variant of uncertain significance. -
not specified Benign:1
Apr 11, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.4941C>A (p.Asn1647Lys) results in a non-conservative amino acid change located in the BRCT domain superfamily of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251200 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Three independent functional studies have reported no damaging effect of this variant including normal transcriptional activity (Lee_2010, Wood_2016), and functional HDR activity (Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 20516115, 30209399, 28781887). ClinVar contains an entry for this variant (Variation ID: 55325). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
Sep 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter