chr2-189805665-C-T

Variant names:

• chr2-189805665-C-T
• NM_000534.5:c.329C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000534.5(PMS1):​c.329C>T​(p.Thr110Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.329C>T	p.Thr110Ile	missense_variant	Exon 4 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.329C>T	p.Thr110Ile	missense_variant	Exon 4 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461334 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726980

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: 9.00e-7

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
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;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;.;.;H;.;H;.;.;H;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.5	.;.;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;.;.;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;.;.;.;.;.
Vest4		0.97, 0.98, 0.98, 0.92, 0.97, 0.98
MutPred		0.75		Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);Loss of catalytic residue at T110 (P = 0.0214);.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr2-190670391;