Genetic Variant MSH2:p.His665Gln (chr2-47475260-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000251.3(MSH2):c.1995C>A(p.His665Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H665Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.866

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]

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 15 uncertain in NM_000251.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25117564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1995C>A	p.His665Gln	missense_variant	Exon 12 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.1995C>A	p.His665Gln	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1442576

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717552

African (AFR)

AF:

0.00

AC:

AN:

33044

American (AMR)

AF:

0.00

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25470

East Asian (EAS)

AF:

0.00

AC:

AN:

38482

South Asian (SAS)

AF:

0.00

AC:

AN:

85792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099312

Other (OTH)

AF:

0.00

AC:

AN:

59130

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.38

T;.;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.24

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

T;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.40

N;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.3

N;N;.;N

REVEL

Uncertain

0.46

Sift

Benign

0.41

T;T;.;T

Sift4G

Benign

0.34

T;T;.;T

Polyphen

0.067

B;.;.;B

Vest4

0.76

MutPred

0.56

Loss of ubiquitination at K661 (P = 0.0837);.;Loss of ubiquitination at K661 (P = 0.0837);Loss of ubiquitination at K661 (P = 0.0837);

MVP

0.89

MPC

0.0072

ClinPred

0.81

GERP RS

3.2

Varity_R

0.46

gMVP

0.67

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over