rs1145234

chr2-189867833-T-Cchr2-189867833-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000534.5(PMS1):c.2377T>C(p.Tyr793His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,579,274 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y793D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.395

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001994431).
• BP6: Variant 2-189867833-T-C is Benign according to our data. Variant chr2-189867833-T-C is described in ClinVar as [Benign]. Clinvar id is 135049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1993/152300) while in subpopulation AFR AF= 0.0448 (1862/41558). AF 95% confidence interval is 0.0431. There are 38 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.2377T>C	p.Tyr793His	missense_variant	11/13	ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.2377T>C	p.Tyr793His	missense_variant	11/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1980 AN: 152182 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00388 AC: 974 AN: 250934 Hom.: 15 AF XY: 0.00307 AC XY: 416 AN XY: 135660

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00158 AC: 2258 AN: 1426974 Hom.: 32 Cov.: 26 AF XY: 0.00141 AC XY: 1003 AN XY: 712012

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00410

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.0131 AC: 1993 AN: 152300 Hom.: 38 Cov.: 32 AF XY: 0.0128 AC XY: 952 AN XY: 74492

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00306 Hom.: 12

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0458 AC: 202

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00449 AC: 545

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	8.9
Dann	Benign	0.66
DEOGEN2	Benign	0.013	T;T;T;.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.076	N
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.54	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;.;.
Vest4		0.093
MVP		0.82
MPC		0.075
ClinPred		0.00056	T
GERP RS		-3.4
Varity_R		0.020
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1145234; hg19: chr2-190732559; COSMIC: COSV99066316; COSMIC: COSV99066316;