chr2-47805000-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000179.3(MSH6):āc.3529C>Gā(p.Leu1177Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L1177I) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3529C>G | p.Leu1177Val | missense_variant | 6/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3529C>G | p.Leu1177Val | missense_variant | 6/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251246Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135792
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461390Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727032
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 09, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 27, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 04, 2023 | This missense variant replaces leucine with valine at codon 1177 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with urothelial carcinoma and suspected of Lynch syndrome (PMID: 35372080). Additionally, in a pancreatic cancer case-control study this variant has been reported in 3/1005 cases and 6/23705 unaffected controls (PMID: 32980694), and in a large breast cancer case-control study this variant has been reported in 1/60466 cases and 6/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD) with all three variant alleles detected in the East Asian population. 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 | clinical testing | Ambry Genetics | Sep 28, 2023 | The p.L1177V variant (also known as c.3529C>G), located in coding exon 6 of the MSH6 gene, results from a C to G substitution at nucleotide position 3529. The leucine at codon 1177 is replaced by valine, an amino acid with highly similar properties. This variant was present with a carrier frequency of 0.00299 in 1005 Japanese pancreatic cancer patients and with a carrier frequency of 0.00025 in 23705 controls (Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This alteration was also identified in an individual diagnosed with an upper tract urothelial carcinoma (Guan B et al. Front Oncol, 2022 Mar;12:774202). This amino acid position is highly 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. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 22, 2023 | This missense variant replaces leucine with valine at codon 1177 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with urothelial carcinoma and suspected of Lynch syndrome (PMID: 35372080). Additionally, in a pancreatic cancer case-control study this variant has been reported in 3/1005 cases and 6/23705 unaffected controls (PMID: 32980694), and in a large breast cancer case-control study this variant has been reported in 1/60466 cases and 6/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD) with all three variant alleles detected in the East Asian population. 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2017 | This variant is denoted MSH6 c.3529C>G at the cDNA level, p.Leu1177Val (L1177V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a breast tumor (Gellert 2016). MSH6 Leu1177Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1177Val occurs at a position that is conserved across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Leu1177Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 25, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at