rs56305733

Positions:

• chr2-189854621-A-C
• 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>C​(p.Gln450Pro) 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. 13/21 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=0.13823694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.1349A>C	p.Gln450Pro	missense_variant	9/13	ENST00000441310.7
LOC105373796	XR_001739151.2	n.319-1764T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.1349A>C	p.Gln450Pro	missense_variant	9/13	1	NM_000534.5	P1

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	0.068
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	6.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T;T;T;.;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	.;.;N;.;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.035	.;.;D;.;D;D;D;D;T
Sift4G	Benign	0.16	.;T;T;T;T;T;T;T;T
Polyphen		0.68, 0.10	.;.;.;P;B;.;.;.;.
Vest4		0.23, 0.23, 0.34, 0.29, 0.24
MutPred		0.33		.;.;.;.;Loss of sheet (P = 0.0084);.;Loss of sheet (P = 0.0084);.;.;
MVP		0.98
MPC		0.073
ClinPred		0.16	T
GERP RS		-0.89
Varity_R		0.14
gMVP		0.37

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;