NM_000535.7(PMS2):c.1501G>A (p.Val501Met) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Jun 21, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001530922.1

Allele description [Variation Report for NM_000535.7(PMS2):c.1501G>A (p.Val501Met)]

NM_000535.7(PMS2):c.1501G>A (p.Val501Met)

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.1501G>A (p.Val501Met)
HGVS:
  • NC_000007.14:g.5987264C>T
  • NG_008466.1:g.26843G>A
  • NM_000535.7:c.1501G>AMANE SELECT
  • NM_001322003.2:c.1096G>A
  • NM_001322004.2:c.1096G>A
  • NM_001322005.2:c.1096G>A
  • NM_001322006.2:c.1345G>A
  • NM_001322007.2:c.1183G>A
  • NM_001322008.2:c.1183G>A
  • NM_001322009.2:c.1096G>A
  • NM_001322010.2:c.940G>A
  • NM_001322011.2:c.568G>A
  • NM_001322012.2:c.568G>A
  • NM_001322013.2:c.928G>A
  • NM_001322014.2:c.1501G>A
  • NM_001322015.2:c.1192G>A
  • NP_000526.2:p.Val501Met
  • NP_001308932.1:p.Val366Met
  • NP_001308933.1:p.Val366Met
  • NP_001308934.1:p.Val366Met
  • NP_001308935.1:p.Val449Met
  • NP_001308936.1:p.Val395Met
  • NP_001308937.1:p.Val395Met
  • NP_001308938.1:p.Val366Met
  • NP_001308939.1:p.Val314Met
  • NP_001308940.1:p.Val190Met
  • NP_001308941.1:p.Val190Met
  • NP_001308942.1:p.Val310Met
  • NP_001308943.1:p.Val501Met
  • NP_001308944.1:p.Val398Met
  • LRG_161t1:c.1501G>A
  • LRG_161:g.26843G>A
  • NC_000007.13:g.6026895C>T
  • NM_000535.5:c.1501G>A
  • NM_000535.6:c.1501G>A
  • NR_136154.1:n.1588G>A
  • p.V501M
Protein change:
V190M
Links:
dbSNP: rs540287433
NCBI 1000 Genomes Browser:
rs540287433
Molecular consequence:
  • NM_000535.7:c.1501G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.1096G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.1096G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.1096G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.1345G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.1183G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.1183G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.1096G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322010.2:c.940G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322011.2:c.568G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322012.2:c.568G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.928G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.1501G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.1192G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.1588G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000697299Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jun 21, 2021)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis.

Vargas-Parra GM, González-Acosta M, Thompson BA, Gómez C, Fernández A, Dámaso E, Pons T, Morak M, Del Valle J, Iglesias S, Velasco À, Solanes A, Sanjuan X, Padilla N, de la Cruz X, Valencia A, Holinski-Feder E, Brunet J, Feliubadaló L, Lázaro C, Navarro M, Pineda M, et al.

Int J Cancer. 2017 Oct 1;141(7):1365-1380. doi: 10.1002/ijc.30820. Epub 2017 Jul 3.

PubMed [citation]
PMID:
28577310

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.

Li S, Qian D, Thompson BA, Gutierrez S, Wu S, Pesaran T, LaDuca H, Lu HM, Chao EC, Black MH.

J Med Genet. 2020 Jan;57(1):62-69. doi: 10.1136/jmedgenet-2019-106096. Epub 2019 Aug 7.

PubMed [citation]
PMID:
31391288
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697299.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: PMS2 c.1501G>A (p.Val501Met) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 364708 control chromosomes, predominantly at a frequency of 7.8e-05 within the Non-Finnish European subpopulation in the gnomAD database (v2.1 exomes- and v3.1 genomes dataset). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than the estimated maximum allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), suggesting that the variant could be a benign polymorphism. However, the variant is located in a region that is highly homologous to a PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. The variant, c.1501G>A, has been reported in the literature as a germline variant in an individual affected with a tumor that belongs to the Lynch syndrome tumor spectrum (Li_2020), and in another individual affected with breast cancer, but was also found in several healthy controls (Dorling_2021, through LOVD). In addition, the variant was reported as somatic variant in a Lynch syndrome-associated tumor (Vargas-Parra_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. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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