NM_000535.7(PMS2):c.2012C>T (p.Thr671Met) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 31, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000212865.27

Allele description [Variation Report for NM_000535.7(PMS2):c.2012C>T (p.Thr671Met)]

NM_000535.7(PMS2):c.2012C>T (p.Thr671Met)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.2012C>T (p.Thr671Met)

HGVS:

NC_000007.14:g.5982986G>A
NG_008466.1:g.31121C>T
NM_000535.7:c.2012C>TMANE SELECT
NM_001322003.2:c.1607C>T
NM_001322004.2:c.1607C>T
NM_001322005.2:c.1607C>T
NM_001322006.2:c.1856C>T
NM_001322007.2:c.1694C>T
NM_001322008.2:c.1694C>T
NM_001322009.2:c.1607C>T
NM_001322010.2:c.1451C>T
NM_001322011.2:c.1079C>T
NM_001322012.2:c.1079C>T
NM_001322013.2:c.1439C>T
NM_001322014.2:c.2012C>T
NM_001322015.2:c.1703C>T
NP_000526.2:p.Thr671Met
NP_001308932.1:p.Thr536Met
NP_001308933.1:p.Thr536Met
NP_001308934.1:p.Thr536Met
NP_001308935.1:p.Thr619Met
NP_001308936.1:p.Thr565Met
NP_001308937.1:p.Thr565Met
NP_001308938.1:p.Thr536Met
NP_001308939.1:p.Thr484Met
NP_001308940.1:p.Thr360Met
NP_001308941.1:p.Thr360Met
NP_001308942.1:p.Thr480Met
NP_001308943.1:p.Thr671Met
NP_001308944.1:p.Thr568Met
LRG_161t1:c.2012C>T
LRG_161:g.31121C>T
NC_000007.13:g.6022617G>A
NM_000535.5:c.2012C>T
NM_000535.6:c.2012C>T
NM_001322014.2:c.2012C>T
NR_136154.1:n.2099C>T
p.T671M

Protein change:

T360M

Links:

dbSNP: rs587780046

NCBI 1000 Genomes Browser:

rs587780046

Molecular consequence:

NM_000535.7:c.2012C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1607C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1607C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1607C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1694C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1694C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1607C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1079C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1079C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1439C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2012C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1703C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2099C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697320	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 19, 2024)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 25186627, 26483394, 27449771, 28135145, 29785153, 31422574, 31159747, 30113427, 30613976, 33471991, 33120919, 35263119, 35402282, 34271781, 35089076, 35372080 Citation Link,
SCV002072015	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002550696	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697320

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 19, 2024)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link,

SCV002072015

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 9, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002550696

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 31, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients.

Hu C, Hart SN, Bamlet WR, Moore RM, Nandakumar K, Eckloff BW, Lee YK, Petersen GM, McWilliams RR, Couch FJ.

Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11. doi: 10.1158/1055-9965.EPI-15-0455. Epub 2015 Oct 19.

PubMed [citation]

PMID:: 26483394
PMCID:: PMC4754121

See all PubMed Citations (17)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697320.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: PMS2 c.2012C>T (p.Thr671Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 168512 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). However, this PMS2 locus is highly homologous to PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.2012C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, ovarian cancer or pancreatic cancer (e.g. Tung 2015, Hu 2016, Yang 2016, Yurgelun 2017, Goidescu 2018, Rizzolo_2019, Tsaousis_2019, Duzkale_2021, Sahin_2022, Abdel-Razeq_2022, Dorling_2021, Delahunty_2022,) but has also been reported in individual(s) without a cancer diagnosis (e.g. Kraemer_2019). One of the reported colorectal cancer patients had a co-occurring pathogenic variant (KRAS c.34G>T, p.Gly12Cys) while the patient's tumor was determined to be MMR proficient and microsatellite stable (Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35402282, 35263119, 33471991, 34271781, 29785153, 35372080, 26483394, 31422574, 30613976, 35089076, 31159747, 25186627, 27449771, 28135145, 33120919, 30113427). ClinVar contains an entry for this variant (Variation ID: 127770). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002072015.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2012C>T, in exon 12 that results in an amino acid change, p.Thr671Met. This sequence change has been described in gnomAD with a frequency of 0.035% in the Non-Finnish European sub-population (dbSNP rs587780046). The p.Thr671Met change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr671Met substitution. The c.2012C>T sequence change has been reported in the literature in individuals affected with breast cancer, colorectal cancer or pancreatic cancer (PMIDs: 25186627, 26483394, 27449771, 28135145, 29785153, 30613976, 31159747) but has also been reported in individuals without a cancer diagnosis (PMID: 31422574). One of the reported colorectal cancer patients also carried a pathogenic variant in the KRAS gene (c.34G>T, p.Gly12Cys). The patient's tumor was determined to be MMR proficient and microsatellite stable (PMID: 28135145). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr671Met change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550696.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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