NM_000251.3:c.1703C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000251.3(MSH2):​c.1703C>A​(p.Thr568Lys) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T568R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MSH2
NM_000251.3 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.46

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • Lynch syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
  • Lynch syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
  • Muir-Torre syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
  • mismatch repair cancer syndrome 1
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • mismatch repair cancer syndrome 2
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • ovarian cancer
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • prostate cancer
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • rhabdomyosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • breast cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13180766).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.1703C>A p.Thr568Lys missense_variant Exon 11 of 16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.1703C>A p.Thr568Lys missense_variant Exon 11 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1426564
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
712030
African (AFR)
AF:
0.00
AC:
0
AN:
32814
American (AMR)
AF:
0.00
AC:
0
AN:
44620
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25898
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39442
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85324
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53340
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5562
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1080464
Other (OTH)
AF:
0.00
AC:
0
AN:
59100
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.066
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
16
DANN
Benign
0.90
DEOGEN2
Benign
0.36
T;.;.;.
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
-0.14
N;.;.;.
PhyloP100
3.5
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.85
N;N;.;N
REVEL
Uncertain
0.39
Sift
Benign
0.55
T;T;.;T
Sift4G
Benign
0.56
T;T;.;T
Polyphen
0.0
B;.;.;B
Vest4
0.47
MutPred
0.51
Gain of ubiquitination at T568 (P = 0.0155);.;Gain of ubiquitination at T568 (P = 0.0155);Gain of ubiquitination at T568 (P = 0.0155);
MVP
0.88
MPC
0.0062
ClinPred
0.68
D
GERP RS
3.6
Varity_R
0.061
gMVP
0.43
Mutation Taster
=42/58
disease causing

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

Other links and lift over

dbSNP: rs1285862035; hg19: chr2-47698145; API