2-189854621-A-G

Position:

• chr2-189854621-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000534.5(PMS1):​c.1349A>G​(p.Gln450Arg) 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. 16/21 in silico tools predict a benign 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: 2.02

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]

LOC105373796 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12542555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS1	NM_000534.5	c.1349A>G	p.Gln450Arg	missense_variant	9/13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.1349A>G	p.Gln450Arg	missense_variant	9/13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.1
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T;T;T;T;T;.;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.61	T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.7	.;.;.;.;L;.;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.84	.;.;N;.;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.082	.;.;T;.;T;T;T;T;T
Sift4G	Benign	0.19	.;T;T;T;T;T;T;T;T
Polyphen		0.040, 0.72	.;.;.;B;P;.;.;.;.
Vest4		0.14, 0.13, 0.17, 0.13, 0.15, 0.13
MutPred		0.28		.;.;.;.;Gain of solvent accessibility (P = 0.0584);.;Gain of solvent accessibility (P = 0.0584);.;.;
MVP		0.98
MPC		0.065
ClinPred		0.17	T
GERP RS		-0.89
Varity_R		0.036
gMVP		0.26

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: rs56305733; hg19: chr2-190719347; COSMIC: COSV100575446; COSMIC: COSV100575446;