Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.1228G>A(p.Ala410Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23985207).
BP6
Variant 17-43094303-C-T is Benign according to our data. Variant chr17-43094303-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246448.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=5}.
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 02, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.1228G>A (p.Ala410Thr) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250802 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1228G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. The following publication has been ascertained in the context of this evaluation (PMID: 32546644). ClinVar contains an entry for this variant (Variation ID: 246448). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.A410T variant (also known as c.1228G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1228. The alanine at codon 410 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
not provided Uncertain:1
Feb 29, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.1228G>A at the cDNA level, p.Ala410Thr (A410T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 c.1347G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala410Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ala410Thr occurs at a position that is not conserved and is located in a binding domain known to interact with multiple proteins (Zhang 1998, Chai 1999, Narod 2004, Harte 2010, Zhong 1999). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ala410Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 410 of the BRCA1 protein (p.Ala410Thr). This variant is present in population databases (rs779974365, gnomAD 0.007%). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 246448). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
May 20, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is considered benign. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -