rs200056411

chr2-47470983-T-Achr2-47470983-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000251.3(MSH2):c.1680T>A(p.Asn560Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N560I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.581

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 4 ACMG points.

• PM1: In a hotspot region, there are 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1680T>A	p.Asn560Lys	missense_variant	11/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1680T>A	p.Asn560Lys	missense_variant	11/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D;D;.;D
REVEL	Uncertain	0.63
Sift	Benign	0.33	T;T;.;T
Sift4G	Benign	0.24	T;T;.;T
Polyphen		0.99	D;.;.;D
Vest4		0.80
MutPred		0.57		Loss of ubiquitination at K555 (P = 0.0261);.;Loss of ubiquitination at K555 (P = 0.0261);Loss of ubiquitination at K555 (P = 0.0261);
MVP		0.92
MPC		0.032
ClinPred		1.0	D
GERP RS		-1.9
Varity_R		0.66
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47698122;