rs121434629

Variant names:

• chr7-6005918-C-A
• rs121434629
• NM_000535.7:c.137G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-6005918-C-A
• chr7-6005918-C-T
• chr7-6005918-C-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS3 PM5 PP3_Strong PP5_Very_Strong BS1_Supporting

The NM_000535.7(PMS2):​c.137G>T​(p.Ser46Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,610,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000469744: Borras et al. (2013) demonstrated through in vitro expressions studies that the p.Ser46Ile variant had significantly reduced mismatch repair activity, approximately 13% that of wild type, while Drost et al. (2013) showed that the p.Ser46Ile variant had a mismatch repair efficiency similar to that of a known pathogenic variant." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:51 O:1
• Conservation: PhyloP100: 7.54
• Publications: 85 publications found

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000469744: Borras et al. (2013) demonstrated through in vitro expressions studies that the p.Ser46Ile variant had significantly reduced mismatch repair activity, approximately 13% that of wild type, while Drost et al. (2013) showed that the p.Ser46Ile variant had a mismatch repair efficiency similar to that of a known pathogenic variant.; SCV000840051: "In addition, functional studies have shown that the c.137G>T (p.S46I) variant significantly impairs mismatch repair activity (PMID: 23709753, 24027009)."; SCV004019868: Functional studies indicate this variant impacts protein function [PMID: 24027009, 23709753, 27435373, 30608896, 17557300].; SCV004031230: "functional studies support that the variant impairs mismatch repair activity (PMID: 23709753)."; SCV000108292: deficient protein function inferred from 2 independent assays; SCV000271259: In vitro functional studies provide some evidence that the p.Ser46Ile variant may impact protein function (Borras 2013 PMID:23709753, Drost 2013 PMID:24027009, Nakagawa 2004 PMID:15256438).; SCV000918033: Functional studies have shown the variant to cause deficient MMR activity (Borras 2013, Drost 2013, van der Klift 2016).; SCV004842155: Experimental studies showed this variant resulted in impaired mismatch repair activity and negative functional impact on the protein (PMID: 23709753, 24027009).; SCV000686122: Functional studies have shown that this variant significantly impairs the mismatch repair activity of PMS2 protein (PMID: 23709753, 24027009).; SCV006306110: "Functional assays at the protein level demostrated abrogated MMR function, proficient expression and nuclear localization (PMID: 23709753, 24027009) (PS3)."; SCV000149566: Published functional studies demonstrate a damaging effect: in vitro cell-free complementation assays showed deficient mismatch repair activity as well as reduced PMS2 expression (Nakagawa 2004, Borras 2013, Drost 2013).; SCV000601815: "In addition, experimental studies have shown this variant causes significantly reduced DNA mismatch repair activity in vitro (PMIDs: 30608896 (2019), 24027009 (2013), 23709753 (2013))."; SCV000604885: "both the p.Ser46Ile and p.Ser46Asn variants exhibit less than 10% of wild-type activity in mismatch repair in vitro assays" (Borras 2013, Drost 2013).; SCV002072174: "In vitro functional assays demonstrate decreased mismatch repair activity for the Ser46Ile variant compared to wild type." PMID:23709753; SCV004223967: PS3; SCV000253845: Experimental studies have shown that this missense change affects PMS2 function (PMID: 23709753, 24027009).; SCV000592923: Functional assays have shown that this variant had reduced mismatch repair efficiency (Drost 2013) and resulted in near absence of the PMS2 protein (Auclair 2007).; SCV004046408: "In vitro experimental studies have shown that this variant impairs the mismatch repair activity of PMS2." PMID:23709753, PMID:24027009; SCV005045097: Functional studies show deficient mismatch repair activity, indicating that this variant impacts protein function (Borras E et al., PMID: 23709753; Drost M et al., PMID: 24027009; van der Klift HM et al., PMID: 27435373).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-6005918-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 91301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 7-6005918-C-A is Pathogenic according to our data. Variant chr7-6005918-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9245.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000294 (429/1458548) while in subpopulation NFE AF = 0.000358 (398/1111820). AF 95% confidence interval is 0.000328. There are 0 homozygotes in GnomAdExome4. There are 187 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.137G>T	p.Ser46Ile	missense	Exon 2 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.323G>T	p.Ser108Ile	missense	Exon 3 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.137G>T	p.Ser46Ile	missense	Exon 2 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.137G>T	p.Ser46Ile	missense	Exon 2 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.137G>T	p.Ser46Ile	missense	Exon 2 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.137G>T		non_coding_transcript_exon	Exon 2 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 40 AN: 245780 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000294 AC: 429 AN: 1458548 Hom.: 0 Cov.: 31 AF XY: 0.000258 AC XY: 187 AN XY: 725594

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.000224 AC: 10 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000358 AC: 398 AN: 1111820

Other (OTH) AF: 0.000349 AC: 21 AN: 60194

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.000327 AC: 5 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000214 AC: 1

ExAC AF: 0.000128 AC: 15

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
16	-	-	not provided (16)
12	-	-	Lynch syndrome 4 (12)
5	-	-	Hereditary cancer-predisposing syndrome (5)
5	-	-	Lynch syndrome (5)
2	-	-	Inherited MMR deficiency (Lynch syndrome) (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9 (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 1 (2)
1	-	-	Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)
1	-	-	Mismatch repair cancer syndrome 1 (1)
1	-	-	Mismatch repair cancer syndrome 4 (1)
1	-	-	Pituitary carcinoma (1)
1	-	-	PMS2-related cancer disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.98
MPC		0.29
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.83
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434629; hg19: chr7-6045549; COSMIC: COSV56151410;