chr2-47478478-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP3BP6

The NM_000251.3(MSH2):​c.2417C>G​(p.Thr806Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,792 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T806I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

3
13
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.49

Publications

2 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 2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 35 uncertain in NM_000251.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.781
BP6
Variant 2-47478478-C-G is Benign according to our data. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.2417C>G p.Thr806Ser missense_variant Exon 14 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.2417C>G p.Thr806Ser missense_variant Exon 14 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251392
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS 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:
0.00000958
AC:
14
AN:
1461792
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727192
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39680
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000989
AC:
11
AN:
1111972
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.468
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Feb 12, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.T806S variant (also known as c.2417C>G), located in coding exon 14 of the MSH2 gene, results from a C to G substitution at nucleotide position 2417. The threonine at codon 806 is replaced by serine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 18, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.63
D;.;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.78
D;D;D;D
MetaSVM
Uncertain
0.43
D
MutationAssessor
Benign
1.6
L;.;.;.
PhyloP100
7.5
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.6
D;D;.;D
REVEL
Uncertain
0.60
Sift
Benign
0.20
T;T;.;T
Sift4G
Uncertain
0.056
T;T;.;D
Polyphen
0.98
D;.;.;D
Vest4
0.76
MutPred
0.49
Gain of disorder (P = 0.0766);.;Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);
MVP
0.83
MPC
0.033
ClinPred
0.90
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.43
gMVP
0.63
Mutation Taster
=62/38
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
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

Other links and lift over

dbSNP: rs758889557; hg19: chr2-47705617; API