rs1114167854

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000251.3(MSH2):​c.1757C>G​(p.Ser586Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S586S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 stop_gained, splice_region

Scores

5
1
1
Splicing: ADA: 0.9877
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.50
Variant links:
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 2-47471060-C-G is Pathogenic according to our data. Variant chr2-47471060-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 428519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47471060-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSH2NM_000251.3 linkuse as main transcriptc.1757C>G p.Ser586Ter stop_gained, splice_region_variant 11/16 ENST00000233146.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1757C>G p.Ser586Ter stop_gained, splice_region_variant 11/161 NM_000251.3 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
20
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 03, 2023This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 16, 2016This variant is denoted MSH2 c.1757C>G at the cDNA level and p.Ser586Ter (S586X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in an individual with Lynch syndrome and is considered pathogenic (De Lellis 2013). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 26, 2020The p.S586* pathogenic mutation (also known as c.1757C>G), located in coding exon 11 of the MSH2 gene, results from a C to G substitution at nucleotide position 1757. This changes the amino acid from a serine to a stop codon within coding exon 11. This alteration was detected in 1/132 unrelated individuals who met either Amsterdam I or Amsterdam II criteria. (De Lellis L et al. PLoS ONE, 2013 Nov;8:e81194). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
50
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.89
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Benign
0.70
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1114167854; hg19: chr2-47698199; API