chr2-47466808-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000251.3(MSH2):c.1661G>A(p.Ser554Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S554C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
MSH2
NM_000251.3 missense, splice_region
NM_000251.3 missense, splice_region
Scores
1
11
7
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.96
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.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 uncertain in NM_000251.3
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr2-47466807-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 90718.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-47466808-G-A is Pathogenic according to our data. Variant chr2-47466808-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 483664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47466808-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1661G>A | p.Ser554Asn | missense_variant, splice_region_variant | 10/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1661G>A | p.Ser554Asn | missense_variant, splice_region_variant | 10/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ExAC
?
AF:
AC:
1
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lynch syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 03, 2023 | This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205]. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 554 of the MSH2 protein (p.Ser554Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 81 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs63750597, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancers (PMID: 21778331, 23523604). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 483664). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 10 (PMID: 19250818). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2022 | The c.1661G>A pathogenic mutation (also known as p.S554N), located in coding exon 10 of the MSH2 gene, results from a G to A substitution at nucleotide position 1661. The serine at codon 554 is replaced by asparagine, an amino acid with highly similar properties. However, this change occurs in the last base pair of exon 10, which makes it likely to have some effect on normal mRNA splicing. This mutation was previously identified in one family fulfilling Amsterdam criteria; further functional analysis of this alteration showed abolishment of the native donor site and a deletion of the last 81 base pairs of exon 10 (Perez-Cabornero L et al. Eur. J. Cancer. 2009 May;45:1485-93; Pérez-Cabornero L et al. Cancer Prev Res (Phila). 2011 Oct;4:1546-55). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 18, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N
REVEL
Uncertain
Sift
Benign
T;T;.;T
Sift4G
Benign
T;T;.;T
Polyphen
B;.;.;B
Vest4
MutPred
Loss of catalytic residue at K555 (P = 0.049);.;Loss of catalytic residue at K555 (P = 0.049);Loss of catalytic residue at K555 (P = 0.049);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at