chr2-189818038-G-A

Variant names:

• chr2-189818038-G-A
• rs113137368
• NM_000534.5:c.440G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000534.5(PMS1):​c.440G>A​(p.Arg147Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283
• Publications: 0 publications found

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]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07351908).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	NM_000534.5	MANE Select	c.440G>A	p.Arg147Lys	missense	Exon 5 of 13	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.440G>A	p.Arg147Lys	missense	Exon 6 of 14	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.440G>A	p.Arg147Lys	missense	Exon 5 of 13	NP_001307976.1	P54277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.440G>A	p.Arg147Lys	missense	Exon 5 of 13	ENSP00000406490.3	P54277-1
	PMS1	ENST00000424059.1	TSL:1	n.440G>A		non_coding_transcript_exon	Exon 4 of 9
	PMS1	ENST00000921104.1		c.440G>A	p.Arg147Lys	missense	Exon 5 of 14	ENSP00000591163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.6
DANN	Benign	0.66
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.30	N
PhyloP100		0.28
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.84
MPC		0.060
ClinPred		0.031	T
GERP RS		-4.3
PromoterAI		-0.0070	Neutral
Varity_R		0.047
gMVP		0.34
Mutation Taster		=293/7	polymorphism

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

Other links and lift over

dbSNP: rs113137368; hg19: chr2-190682764; COSMIC: COSV59714884; COSMIC: COSV59714884;