rs1064794109

chr2-47429773-G-Achr2-47429773-G-Cchr2-47429773-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000251.3(MSH2):c.1108G>A(p.Ala370Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. A370G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.58

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104135126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1108G>A	p.Ala370Thr	missense_variant	7/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1108G>A	p.Ala370Thr	missense_variant	7/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251272 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 2023	The p.A370T variant (also known as c.1108G>A), located in coding exon 7 of the MSH2 gene, results from a G to A substitution at nucleotide position 1108. The alanine at codon 370 is replaced by threonine, an amino acid with similar properties. This alteration was reported in a Taiwanese family meeting Amsterdam criteria II (Tang R et al. Clin. Genet. 2009 Apr;75:334-45). However, in a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175).This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 12, 2019	This missense variant replaces alanine with threonine at codon 370 of the MSH2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported this variant to be functional in binding to MSH6 in a yeast two-hybrid assay (PMID: 29731845). This variant has been reported in a Lynch syndrome family (PMID: 19419416). This variant has been identified in 3/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2016

This variant is denoted MSH2 c.1108G>A at the cDNA level, p.Ala370Thr (A370T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has been observed in at least one family with Lynch syndrome (Tang 2009). MSH2 Ala370Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ala370Thr occurs at a position that is not conserved and is located within the lever domain (Lutzen 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH2 Ala370Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	17
Dann	Benign	0.34
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.12	N;.;.;.
MutationTaster	Benign	0.62	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.66	N;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.0	B;.;.;B
Vest4		0.37
MutPred		0.43		Gain of disorder (P = 0.168);.;Gain of disorder (P = 0.168);Gain of disorder (P = 0.168);
MVP		0.93
MPC		0.0066
ClinPred		0.15	T
GERP RS		4.7
Varity_R		0.26
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1064794109; hg19: chr2-47656912;