chr2-47466807-A-G

Position:

• chr2-47466807-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_000251.3(MSH2):​c.1660A>G​(p.Ser554Gly) 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 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
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 6.56

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• 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 Lovd as [Pathogenic].
• PP5: Variant 2-47466807-A-G is Pathogenic according to our data. Variant chr2-47466807-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 90717.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47466807-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1660A>G	p.Ser554Gly	missense_variant, splice_region_variant	10/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1660A>G	p.Ser554Gly	missense_variant, splice_region_variant	10/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

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]. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Variant causes splicing aberration leading to frameshift: full inactivation of variant allele -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.1660A>G variant (also known as p.S554G), located in coding exon 10 of the MSH2 gene, results from an A to G substitution at nucleotide position 1660. The serine at codon 554 is replaced by glycine, an amino acid with similar properties. In one study, this variant was detected in a colorectal cancer patient meeting Amsterdam I criteria whose tumor showed loss of MSH2 expression on immunohistochemistry (IHC) (Casey G et al. JAMA, 2005 Feb;293:799-809). This alteration has also been identified as germline as well as somatic in individuals whose Lynch syndrome-associated tumors displayed loss of MSH2 and/or MSH6 on IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Conversion analysis performed in this study revealed c.1660A>G was associated with out-of-frame skipping of exon 10 (Casey G et al. JAMA, 2005 Feb;293:799-809). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 14, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2023

Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 15713769). 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. ClinVar contains an entry for this variant (Variation ID: 90717). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15713769). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 554 of the MSH2 protein (p.Ser554Gly). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	2.0	M;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Uncertain	0.57
Sift	Benign	0.066	T;T;.;T
Sift4G	Benign	0.29	T;T;.;T
Polyphen		0.011	B;.;.;B
Vest4		0.74
MutPred		0.63		Loss of ubiquitination at K555 (P = 0.0992);.;Loss of ubiquitination at K555 (P = 0.0992);Loss of ubiquitination at K555 (P = 0.0992);
MVP		0.96
MPC		0.0070
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751656; hg19: chr2-47693946;