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rs267607938

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBP6_Strong

The NM_000251.3(MSH2):c.991A>G(p.Asn331Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,828 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N331S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

4
11
4

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:5

Conservation

PhyloP100: 9.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 14 uncertain in NM_000251.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899
BP6
Variant 2-47416344-A-G is Benign according to our data. Variant chr2-47416344-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 91271.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr2-47416344-A-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.991A>G p.Asn331Asp missense_variant 6/16 ENST00000233146.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.991A>G p.Asn331Asp missense_variant 6/161 NM_000251.3 P1P43246-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152236
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251462
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1459592
Hom.:
0
Cov.:
29
AF XY:
0.0000207
AC XY:
15
AN XY:
726328
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.0000264
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4Benign:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Lynch syndrome 1 Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingCounsylNov 01, 2017- -
Uncertain significance, reviewed by expert panelcurationInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Jun 13, 2018Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.091) -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 21, 2023This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 13, 2018This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 02, 2022- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 26, 2022Variant summary: MSH2 c.991A>G (p.Asn331Asp) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 5/5 computational tools predict no significant impact on normal splicing and ESE finder predicts that this variant may eliminate a SRp55 site and create a SRp40 site. These predictions have been tested functionally through a minigene assay which confirmed that the variant does not affect splicing, despite splicing computational tools suggesting ESE sites are predicted to be affected (Tournier_2008). However, a cell-free in vitro MMR activity assay showed that this variant had 62.4% MMR activity (Drost_2019). c.991A>G has been reported in the literature in individuals affected with Lynch Syndrome and breast cancer (Tung_2015, Tournier_2008, Spaepen_2006). One of the studies carried out additional analysis: tumor tissue from a patient was tested for microsatellite instability (0 of 10 loci were unstable), MSH2 protein expression (immunostaining showed both MSH2 and MLH1 as positive), and segregation with disease in the family (the variant did not segregate with disease in the 3 family members tested). Together, these analyses suggest the variant does not contribute to tumorigenesis (Spaepen_2006). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=4) including an expert panel (InSiGHT), following a recent re-classification, citing the variant as uncertain significance (originally classified as likely benign in 2013) citing new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.091). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 06, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate decreased mismatch repair activity, but no effect on splicing, binding partner interaction, and nuclear localization (Tournier et al., 2008; Drost et al., 2018); Observed in individuals with colorectal or breast cancer (Spaepen et al., 2006; Tung et al., 2015); This variant is associated with the following publications: (PMID: 24362816, 22290698, 16736289, 18561205, 25871441, 25186627, 29179779, 30212499, 30504929, 21120944, 18822302) -
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 27, 2021- -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.054
T
BayesDel_noAF
Uncertain
0.020
Cadd
Benign
21
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;.;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.0
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.4
D;D;.;D
REVEL
Pathogenic
0.76
Sift
Benign
0.18
T;T;.;T
Sift4G
Benign
0.25
T;T;.;T
Polyphen
0.069
B;.;.;D
Vest4
0.86
MutPred
0.81
Gain of ubiquitination at K332 (P = 0.0475);.;Gain of ubiquitination at K332 (P = 0.0475);Gain of ubiquitination at K332 (P = 0.0475);
MVP
0.94
MPC
0.0093
ClinPred
0.59
D
GERP RS
4.5
Varity_R
0.59
gMVP
0.65

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

LitVar

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

Other links and lift over

dbSNP: rs267607938; hg19: chr2-47643483; API