chr2-47783337-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong
The NM_000179.3(MSH6):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,610,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35T) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.104C>T | p.Ala35Val | missense_variant | 1/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.104C>T | p.Ala35Val | missense_variant | 1/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000425 AC: 1AN: 235130Hom.: 0 AF XY: 0.00000771 AC XY: 1AN XY: 129684
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1458186Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7AN XY: 725366
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2024 | The p.A35V variant (also known as c.104C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 104. The alanine at codon 35 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 06, 2023 | This missense variant replaces alanine with valine at codon 35 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/235130 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2019 | Variant summary: MSH6 c.104C>T (p.Ala35Val) results in a non-conservative amino acid change in 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 4.3e-06 in 235130 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.104C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2015 | This variant is denoted MSH6 c.104C>T at the cDNA level, p.Ala35Val (A35V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala35Val 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. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala35Val occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Ala35Val is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 28, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at