chr2-47416321-C-A

Position:

• chr2-47416321-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000251.3(MSH2):​c.968C>A​(p.Ser323Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S323C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91

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.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47416321-C-A is Pathogenic according to our data. Variant chr2-47416321-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.968C>A	p.Ser323Tyr	missense_variant	6/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.968C>A	p.Ser323Tyr	missense_variant	6/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460304 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726622

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Benign	-0.071
Eigen_PC	Benign	0.043
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.1	D;D;.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.012	D;D;.;D
Sift4G	Benign	0.58	T;T;.;T
Polyphen		0.12	B;.;.;P
Vest4		0.48
MutPred		0.53		Loss of disorder (P = 0.0129);.;Loss of disorder (P = 0.0129);Loss of disorder (P = 0.0129);
MVP		0.94
MPC		0.011
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.24

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: rs63750732; hg19: chr2-47643460;