2-47466808-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):c.1661G>C(p.Ser554Thr) 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: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• 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]

ACMG classification

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-C is Pathogenic according to our data. Variant chr2-47466808-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 90724.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47466808-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1661G>C	p.Ser554Thr	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>C	p.Ser554Thr	missense_variant, splice_region_variant	10/16	1	NM_000251.3	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 03, 2023

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15365996]. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Variant causes splicing aberration (full inactivation of variant allele) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

The c.1661G>C pathogenic mutation (also known as p.S554T), located in coding exon 10 of the MSH2 gene, results from a G to C substitution at nucleotide position 1661. This change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. In addition, this alteration changes the serine at codon 554 to threonine, an amino acid with similar properties. This mutation was first described in a German patient meeting Amsterdam I criteria, who had rectal cancer at 59 years of age and whose tumor was absent for MSH2 on IHC and showed high microsatellite instability. Family history included a mother and brother with colon cancer at 43 and 31 years of age, respectively. RT-PCR analysis of mRNA revealed skipping of exon 10, which the authors concluded established the pathogenicity of this alteration (Kruger S et al. Hum Mutat. 2004;24(4):351-2). One study described another mutation at this nucleotide position (c.1661G>A), which was detected in a large Lynch syndrome family (44 individuals tested). The proband was diagnosed with cancer of the colon-rectum, rectum-sigma at 47 years of age, and his tumor was absent for MSH2/MSH6 and showed high microsatellite instability. Functional analysis showed that this mutation abolished the consensus splice donor site and resulted in the deletion of 81 bp in the mRNA (Perez-Cabornero L et al. Eur J Cancer. 2009 May;45(8):1485-93). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. Based on the available evidence to date, this alteration is classified as a pathogenic mutation. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 19, 2023

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. 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 is associated with altered splicing resulting in skipping of exon 10 (PMID: 15365996). 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: 90724). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 15365996). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 554 of the MSH2 protein (p.Ser554Thr). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	27
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Uncertain	0.61
Sift	Benign	0.15	T;T;.;T
Sift4G	Benign	0.37	T;T;.;T
Polyphen		0.12	B;.;.;P
Vest4		0.67
MutPred		0.62		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		0.92
MPC		0.0091
ClinPred		0.87	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750597; hg19: chr2-47693947;