rs61736576

chr2-189854915-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000534.5(PMS1):c.1643A>G(p.Lys548Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00091 in 1,605,128 control chromosomes in the GnomAD database, including 8 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (6 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.86

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043103397).
• BP6: Variant 2-189854915-A-G is Benign according to our data. Variant chr2-189854915-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 135051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.1643A>G	p.Lys548Arg	missense_variant	9/13	ENST00000441310.7
LOC105373796	XR_001739151.2	n.319-2058T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.1643A>G	p.Lys548Arg	missense_variant	9/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 658 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00120 AC: 298 AN: 248890 Hom.: 0 AF XY: 0.000846 AC XY: 114 AN XY: 134786

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.000551 AC: 801 AN: 1452794 Hom.: 6 Cov.: 28 AF XY: 0.000484 AC XY: 350 AN XY: 723138

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.000999

GnomAD4 genome AF: 0.00433 AC: 660 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74490

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.00465

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 13, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 23, 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	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.0099	T;T;T;T;T;.;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;.;T;T;T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	0.55	D;D;D;D;D;D
PrimateAI	Benign	0.32	T
Polyphen		0.18, 0.018	.;.;.;B;B;.;.;.;.
Vest4		0.051, 0.055, 0.10, 0.057, 0.089, 0.074
MVP		0.91
MPC		0.076
ClinPred		0.0023	T
GERP RS		1.4
Varity_R		0.028
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: rs61736576; hg19: chr2-190719641; COSMIC: COSV99066314; COSMIC: COSV99066314;