rs777351049

Positions:

• chr2-47403207-A-G
• chr2-47403207-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000251.3(MSH2):​c.16A>G​(p.Lys6Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000968 in 1,446,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000097 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 5.03

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36548078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.16A>G	p.Lys6Glu	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.16A>G	p.Lys6Glu	missense_variant	1/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000451 AC: 1 AN: 221766 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 120834

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: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000968 AC: 14 AN: 1446748 Hom.: 0 Cov.: 31 AF XY: 0.00000974 AC XY: 7 AN XY: 718410

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000994

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 27, 2021	The p.K6E variant (also known as c.16A>G), located in coding exon 1 of the MSH2 gene, results from an A to G substitution at nucleotide position 16. The lysine at codon 6 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 09, 2023	This missense variant replaces lysine with glutamic acid at codon 6 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 33471991), as well as healthy individuals (PMID: 29641532, 33471991). This variant has been identified in 1/221766 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 08, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 18822302, 21120944, 29641532, 34326862) -

Lynch syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 22, 2024

- -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 23, 2023

This missense variant replaces lysine with glutamic acid at codon 6 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 33471991), as well as healthy individuals (PMID: 29641532, 33471991). This variant has been identified in 1/221766 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	0.76	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.79	N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.27	T;.;T
Sift4G	Benign	0.35	T;.;T
Polyphen		0.0	B;.;P
Vest4		0.62
MutPred		0.35		Loss of ubiquitination at K6 (P = 0.0074);Loss of ubiquitination at K6 (P = 0.0074);Loss of ubiquitination at K6 (P = 0.0074);
MVP		0.92
MPC		0.0060
ClinPred		0.68	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.82
gMVP		0.42

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: rs777351049; hg19: chr2-47630346;