2-189863774-C-G

Variant names:

• chr2-189863774-C-G
• rs139932286
• NM_000534.5:c.1888C>G

Variant summary

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

The NM_000534.5(PMS1):​c.1888C>G​(p.Arg630Gly) 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.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• 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

ENSG00000300477 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1888C>G	p.Arg630Gly	missense	Exon 10 of 13	NP_000525.1
	PMS1	NM_001321045.2		c.1888C>G	p.Arg630Gly	missense	Exon 11 of 14	NP_001307974.1
	PMS1	NM_001321047.2		c.1888C>G	p.Arg630Gly	missense	Exon 10 of 13	NP_001307976.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.1888C>G	p.Arg630Gly	missense	Exon 10 of 13	ENSP00000406490.3
	PMS1	ENST00000409593.5	TSL:1	c.1212-4025C>G		intron	N/A	ENSP00000387169.1
	PMS1	ENST00000424059.1	TSL:1	n.1771C>G		non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.9
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.49
MutPred		0.57		Loss of MoRF binding (P = 0.0047)
MVP		1.0
MPC		0.41
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.70
gMVP		0.36
Mutation Taster		=61/39	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: rs139932286; hg19: chr2-190728500; COSMIC: COSV59716761;