rs116373169

Variant names:

• chr7-6002607-G-A
• rs116373169
• NM_000535.7:c.383C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-6002607-G-A
• chr7-6002607-G-C
• chr7-6002607-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000535.7(PMS2):​c.383C>T​(p.Ser128Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000379 in 1,611,822 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S128P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:17
• Conservation: PhyloP100: 5.90
• Publications: 13 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: ClinGen, Orphanet
• Lynch syndrome 4

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0128156245).
• BP6: Variant 7-6002607-G-A is Benign according to our data. Variant chr7-6002607-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135943.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00173 (264/152320) while in subpopulation AFR AF = 0.00575 (239/41566). AF 95% confidence interval is 0.00515. There are 6 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.383C>T	p.Ser128Leu	missense_variant	Exon 5 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.383C>T	p.Ser128Leu	missense_variant	Exon 5 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000514 AC: 129 AN: 251142 AF XY: 0.000413

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000238 AC: 347 AN: 1459502 Hom.: 1 Cov.: 31 AF XY: 0.000222 AC XY: 161 AN XY: 726058

African (AFR) AF: 0.00494 AC: 165 AN: 33402

American (AMR) AF: 0.000134 AC: 6 AN: 44714

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86160

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111646

Other (OTH) AF: 0.000565 AC: 34 AN: 60204

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152320 Hom.: 6 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74474

African (AFR) AF: 0.00575 AC: 239 AN: 41566

American (AMR) AF: 0.000327 AC: 5 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68042

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.00178

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000758 AC: 92

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Feb 01, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.383C>T variant affects a conserved nucleotide, resulting in amino acid change from Ser to Leu. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 92/121400 control chromosomes at a frequency of 0.0007578, which is about 7 times of maximal expected frequency of a pathogenic allele (0.0001136), suggesting this variant is benign. Sequence alignment suggests alleles identified in ExAC controls are unlikely from PMS2 pseudogenes. In addition, multiple clinical laboratories/literature classified this variant as benign/likely benign/polymorphisms. Taken together, this variant was classified as likely benign. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BP4 -

Dec 28, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.383C>T; p.Ser128Leu variant (rs116373169) is reported in the literature in an individual with suspected Lynch syndrome, although its clinical significance in this individual was uncertain (Borras 2017). This variant is found in the African population with an allele frequency of 0.5% (136/24972 alleles, including 1 homozygote) in the Genome Aggregation Database, and it is reported as benign/likely benign by multiple laboratories in ClinVar (Variation ID: 135943). The serine at codon 128 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.413). Our laboratory has identified this variant in an individual who also carried a pathogenic truncating PMS2 variant. Although the evidence suggests this variant may be likely benign, there is currently insufficient information to classify with certainty. Therefore, based on available information, the clinical significance of this variant is uncertain at this time. References: Borras E et al. In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation. Cancer Prev Res (Phila). 2017 Oct;10(10):580-587. PMID: 28765196. -

Sep 11, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31433215, 28211887, 28765196, 28873162, 27930734, 20205264) -

Mar 09, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Oct 28, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 26, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 23, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4 Benign:3

Aug 18, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 04, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1 Benign:1

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2 NM_000535.5:c.383C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Uncertain:1

-

Ding PR Lab, Sun Yat-sen University Cancer Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Nov 22, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Ser128Leu variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (Vaughn 2010). The variant was also identified in dbSNP (ID: rs116373169) as "With other allele", ClinVar (classified as benign by Invitae and one other submitter; as likely benign by Ambry Genetics, GeneDx, and five other submitters; and as uncertain significance by one submitter), Cosmic (1x in skin tissue), and MutDB. The variant was not identified in COGR, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in control databases in 188 of 276898 chromosomes (1 homozygous) at a frequency of 0.0007, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 134 of 24038 chromosomes (freq: 0.006), Latino in 3 of 34420 chromosomes (freq: 0.00009), European in 43 of 126388 chromosomes (freq: 0.0003), East Asian in 7 of 18870 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, or Finnish populations. The p.Ser128 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.
Eigen	Benign	-0.00041
Eigen_PC	Benign	-0.062
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;.;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Uncertain	2.8	M;.;.;M
PhyloP100		5.9
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.4	D;D;.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D;D;.;T
Sift4G	Uncertain	0.0040	D;D;.;T
Polyphen		0.86	P;P;P;P
Vest4		0.43
MVP		0.84
MPC		0.25
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.34
Mutation Taster		=98/2	polymorphism

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: rs116373169; hg19: chr7-6042238; COSMIC: COSV56222336; COSMIC: COSV56222336;