chr2-47799813-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000179.3(MSH6):āc.1830G>Cā(p.Lys610Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K610E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1830G>C | p.Lys610Asn | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1830G>C | p.Lys610Asn | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250542Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135702
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727238
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2022 | The p.K610N variant (also known as c.1830G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1830. The lysine at codon 610 is replaced by asparagine, an amino acid with similar properties. This alteration was detected once in a cohort of 1893 women with epithelial ovarian cancer from three population-based studies who were ascertained for mutations in MLH1, MSH2 and MSH6 (Pal T et al. Br. J. Cancer, 2012 Nov;107:1783-90). A different nucleotide change at this position (c.1830G>T) leading to the same amino acid substitution has been identified in a Danish Lynch syndrome cohort and was shown to have intact mismatch repair activity in vitro (Nilbert M et al, Fam. Cancer 2009; 8(1):75-83. Drost M et al, Hum. Mutat. 2012 Mar; 33(3):488-94). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 01, 2022 | This missense variant replaces lysine with asparagine at codon 610 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 been reported in one individual affected with ovarian cancer (PMID: 23047549). However, another variant with a different nucleotide change resulting in the same amino acid (c.1830G>T, p.Lys610Asn) has been reported to retain wild-type mismatch repair function fully (PMID: 22102614), and it has been observed in two individuals affected with Lynch syndrome (PMID: 18566915). This variant has been identified in 2/250542 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 21, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Pal et al., 2012; Dorling et al., 2021); Same amino acid substitution caused by a different nucleotide change (c.1830G>T) has been reported in families with colorectal cancer and demonstrates similar mismatch repair activity relative to wild-type in a functional assay (Nilbert et al., 2009; Drost et al., 2012); This variant is associated with the following publications: (PMID: 22290698, 23621914, 18566915, 17531815, 21120944, 23047549, 33471991, 22102614) - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at