chr2-189818098-A-G

Position:

• chr2-189818098-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000534.5(PMS1):​c.500A>G​(p.Asp167Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,607,734 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.18

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02060318).
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.500A>G	p.Asp167Gly	missense_variant	5/13	ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.500A>G	p.Asp167Gly	missense_variant	5/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000477 AC: 119 AN: 249506 Hom.: 1 AF XY: 0.000519 AC XY: 70 AN XY: 134934

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000690

Gnomad FIN exome AF: 0.00384

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000186 AC: 270 AN: 1455386 Hom.: 3 Cov.: 27 AF XY: 0.000206 AC XY: 149 AN XY: 724378

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000686

Gnomad4 FIN exome AF: 0.00279

Gnomad4 NFE exome AF: 0.0000479

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39 AN XY: 74504

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000538 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000395 AC: 48

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS1 p.Asp167Gly variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs200244068) and in control databases in 134 of 266706 chromosomes (1 homozygous) at a frequency of 0.0005024 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 97 of 25048 chromosomes (freq: 0.003873), South Asian in 21 of 30364 chromosomes (freq: 0.000692), Other in 2 of 6660 chromosomes (freq: 0.0003), European (non-Finnish) in 13 of 117228 chromosomes (freq: 0.000111) and African in 1 of 23510 chromosomes (freq: 0.000043), but was not observed in the Latino, Ashkenazi Jewish, or East Asian populations. The p.Asp167 residue is not conserved in mammals and three of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;T;T;T;.;T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.021	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.1	.;.;.;M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	.;.;.;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	.;.;.;D;D;D;D;D
Sift4G	Uncertain	0.012	.;D;T;D;D;T;D;D
Polyphen		0.95, 0.77, 0.89	.;P;P;P;.;.;.;.
Vest4		0.41, 0.41, 0.42, 0.42
MVP		0.98
MPC		0.31
ClinPred		0.25	T
GERP RS		5.4
Varity_R		0.76
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200244068; hg19: chr2-190682824;