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GeneBe

rs41294984

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000179.3(MSH6):c.194C>G(p.Ser65Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S65S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH6
NM_000179.3 stop_gained

Scores

1
2
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.166
Variant links:
Genes affected
MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47783427-C-G is Pathogenic according to our data. Variant chr2-47783427-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2673637.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSH6NM_000179.3 linkuse as main transcriptc.194C>G p.Ser65Ter stop_gained 1/10 ENST00000234420.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSH6ENST00000234420.11 linkuse as main transcriptc.194C>G p.Ser65Ter stop_gained 1/101 NM_000179.3 P4P52701-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Lynch syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 09, 2023This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.060
Cadd
Pathogenic
35
Dann
Uncertain
0.98
Eigen
Benign
0.18
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.033
N
MutationTaster
Benign
1.0
A;A
Vest4
0.56
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-48010566; API