rs61756360

Variant names:

• chr2-189795860-C-A
• NM_000534.5:c.224C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-189795860-C-A
• chr2-189795860-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000534.5(PMS1):​c.224C>A​(p.Thr75Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.224C>A	p.Thr75Asn	missense_variant	Exon 3 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.224C>A	p.Thr75Asn	missense_variant	Exon 3 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;D;D;D;D;.;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.6	.;.;.;H;.;H;.;.;H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.9	.;.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	.;.;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;.;.;.;.
Vest4		0.93, 0.94, 0.93, 0.92, 0.94
MutPred		0.52		Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);Gain of ubiquitination at K77 (P = 0.0756);
MVP		1.0
MPC		0.40
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.87

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: chr2-190660586; COSMIC: COSV59720526; COSMIC: COSV59720526;