2-47463073-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_000251.3(MSH2):c.1429A>T(p.Asn477Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N477H) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.51

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 15 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-47463073-A-T is Benign according to our data. Variant chr2-47463073-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 629020.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1429A>T	p.Asn477Tyr	missense_variant	9/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1429A>T	p.Asn477Tyr	missense_variant	9/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 15, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2021

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 629020). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 477 of the MSH2 protein (p.Asn477Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.012	D;D;.;D
Sift4G	Uncertain	0.021	D;D;.;D
Polyphen		0.32	B;.;.;P
Vest4		0.75
MutPred		0.49		Loss of disorder (P = 0.0135);.;Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);
MVP		0.93
MPC		0.014
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.54
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs587781346; hg19: chr2-47690212;