rs55859858

chr2-189867873-C-Gchr2-189867873-C-T

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.2417C>G(p.Thr806Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,596,392 control chromosomes in the GnomAD database, including 29 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (12 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.569

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=0.0054065287).
• BP6: Variant 2-189867873-C-G is Benign according to our data. Variant chr2-189867873-C-G is described in ClinVar as [Benign]. Clinvar id is 135047.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00654 (996/152302) while in subpopulation AFR AF= 0.0221 (920/41570). AF 95% confidence interval is 0.0209. There are 17 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.2417C>G	p.Thr806Ser	missense_variant	11/13	ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.2417C>G	p.Thr806Ser	missense_variant	11/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 996 AN: 152186 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00191 AC: 480 AN: 251142 Hom.: 5 AF XY: 0.00144 AC XY: 196 AN XY: 135718

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00261

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000700 AC: 1011 AN: 1444090 Hom.: 12 Cov.: 27 AF XY: 0.000596 AC XY: 429 AN XY: 719722

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.000908

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00654 AC: 996 AN: 152302 Hom.: 17 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74472

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.000953 Hom.: 2

Bravo AF: 0.00722

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00224 AC: 272

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

May 16, 2018

- -

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	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	3.8
Dann	Benign	0.92
DEOGEN2	Benign	0.011	T;T;T;.;.;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0054	T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.37	T;T;T;T;T;T;T
Polyphen		0.0050	.;.;B;.;.;.;.
Vest4		0.15
MutPred		0.20		.;.;Loss of sheet (P = 0.0315);.;.;.;.;
MVP		0.97
MPC		0.056
ClinPred		0.0021	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.034
gMVP		0.25

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: rs55859858; hg19: chr2-190732599;