chr2-47403392-G-C

Position:

• chr2-47403392-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1 PS1_Moderate PM2 BP6

The NM_001258281.1(MSH2):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_001258281.1 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0860

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 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001258281.1 (MSH2) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-47403392-G-C is Benign according to our data. Variant chr2-47403392-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525650.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.201G>C	p.Met67Ile	missense_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.201G>C	p.Met67Ile	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000442 AC: 1 AN: 226206 Hom.: 0 AF XY: 0.00000804 AC XY: 1 AN XY: 124326

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000995

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.91e-7 AC: 1 AN: 1447890 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 67 of the MSH2 protein (p.Met67Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;D;D;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.24	N;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	N;N;N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T;T;T;.;T
Sift4G	Benign	0.21	T;T;T;.;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.081
MutPred		0.61		Gain of catalytic residue at P69 (P = 0.042);.;.;Gain of catalytic residue at P69 (P = 0.042);Gain of catalytic residue at P69 (P = 0.042);
MVP		0.85
MPC		0.0063
ClinPred		0.082	T
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.46
gMVP		0.32

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: rs1442557180; hg19: chr2-47630531;