NM_000535.7(PMS2):c.63_75del (p.Ser22fs) AND Lynch syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 8, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004018094.2

Allele description [Variation Report for NM_000535.7(PMS2):c.63_75del (p.Ser22fs)]

NM_000535.7(PMS2):c.63_75del (p.Ser22fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.63_75del (p.Ser22fs)

HGVS:

NC_000007.14:g.6005980_6005992del
NG_008466.1:g.8115_8127del
NG_050738.1:g.1730_1742del
NM_000535.7:c.63_75delMANE SELECT
NM_001018040.1:c.-343_-331delGTCAGTCCATCAG
NM_001322003.2:c.-343_-331del
NM_001322004.2:c.-242-1934_-242-1922del
NM_001322005.2:c.-343_-331del
NM_001322006.2:c.63_75del
NM_001322007.2:c.-153_-141del
NM_001322008.2:c.-52-1934_-52-1922del
NM_001322009.2:c.-343_-331del
NM_001322010.2:c.-242-1934_-242-1922del
NM_001322011.2:c.-822_-810del
NM_001322012.2:c.-822_-810del
NM_001322013.2:c.-343_-331del
NM_001322014.2:c.63_75del
NM_001322015.2:c.-422_-410del
NM_001406866.1:c.249_261del
NM_001406868.1:c.63_75del
NM_001406869.1:c.63_75del
NM_001406870.1:c.63_75del
NM_001406871.1:c.63_75del
NM_001406872.1:c.63_75del
NM_001406873.1:c.63_75del
NM_001406874.1:c.63_75del
NM_001406875.1:c.-422_-410del
NM_001406876.1:c.-153_-141del
NM_001406877.1:c.-422_-410del
NM_001406878.1:c.-422_-410del
NM_001406879.1:c.-321-1934_-321-1922del
NM_001406880.1:c.-369_-357del
NM_001406881.1:c.-218-1934_-218-1922del
NM_001406882.1:c.-422_-410del
NM_001406883.1:c.-153_-141del
NM_001406884.1:c.63_75del
NM_001406885.1:c.63_75del
NM_001406886.1:c.63_75del
NM_001406887.1:c.-343_-331del
NM_001406888.1:c.-290_-278del
NM_001406889.1:c.-290_-278del
NM_001406890.1:c.-333_-321del
NM_001406891.1:c.-343_-331del
NM_001406892.1:c.-290_-278del
NM_001406893.1:c.-343_-331del
NM_001406894.1:c.-290_-278del
NM_001406895.1:c.-189-1934_-189-1922del
NM_001406896.1:c.-153_-141del
NM_001406897.1:c.-343_-331del
NM_001406898.1:c.-343_-331del
NM_001406899.1:c.-290_-278del
NM_001406900.1:c.-319_-307del
NM_001406901.1:c.-153_-141del
NM_001406902.1:c.-153_-141del
NM_001406903.1:c.-153_-141del
NM_001406904.1:c.-290_-278del
NM_001406905.1:c.-343_-331del
NM_001406906.1:c.-343_-331del
NM_001406907.1:c.-290_-278del
NM_001406908.1:c.-343_-331del
NM_001406909.1:c.-290_-278del
NM_001406910.1:c.-343_-331del
NM_001406911.1:c.-242-1934_-242-1922del
NM_001406912.1:c.63_75del
NP_000526.1:p.Ser22Phefs
NP_000526.2:p.Ser22fs
NP_001308935.1:p.Ser22fs
NP_001308943.1:p.Ser22fs
NP_001393795.1:p.Ser84fs
NP_001393797.1:p.Ser22fs
NP_001393798.1:p.Ser22fs
NP_001393799.1:p.Ser22fs
NP_001393800.1:p.Ser22fs
NP_001393801.1:p.Ser22fs
NP_001393802.1:p.Ser22fs
NP_001393803.1:p.Ser22fs
NP_001393813.1:p.Ser22fs
NP_001393814.1:p.Ser22fs
NP_001393815.1:p.Ser22fs
NP_001393841.1:p.Ser22fs
LRG_161t1:c.63_75del
LRG_161:g.8115_8127del
LRG_161p1:p.Ser22Phefs
NC_000007.13:g.6045611_6045623del
NM_000535.5:c.63_75delGTCAGTCCATCAG
NR_003085.2:n.145_157delGTCAGTCCATCAG
NR_136154.1:n.150_162del

Protein change:

S22fs

Molecular consequence:

NM_001322003.2:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-822_-810del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-822_-810del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-422_-410del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406875.1:c.-422_-410del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406876.1:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406877.1:c.-422_-410del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406878.1:c.-422_-410del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406880.1:c.-369_-357del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406882.1:c.-422_-410del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406883.1:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406887.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406888.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406889.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406890.1:c.-333_-321del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406891.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406892.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406893.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406894.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406896.1:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406897.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406898.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406899.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406900.1:c.-319_-307del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406901.1:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406902.1:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406903.1:c.-153_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406904.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406905.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406906.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406907.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406908.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406909.1:c.-290_-278del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406910.1:c.-343_-331del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322006.2:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322014.2:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406866.1:c.249_261del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406868.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406869.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406870.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406871.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406872.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406873.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406874.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406884.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406885.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406886.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406912.1:c.63_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322004.2:c.-242-1934_-242-1922del - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.-52-1934_-52-1922del - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.-242-1934_-242-1922del - intron variant - [Sequence Ontology: SO:0001627]
NM_001406879.1:c.-321-1934_-321-1922del - intron variant - [Sequence Ontology: SO:0001627]
NM_001406881.1:c.-218-1934_-218-1922del - intron variant - [Sequence Ontology: SO:0001627]
NM_001406895.1:c.-189-1934_-189-1922del - intron variant - [Sequence Ontology: SO:0001627]
NM_001406911.1:c.-242-1934_-242-1922del - intron variant - [Sequence Ontology: SO:0001627]
NR_136154.1:n.150_162del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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DUSP6 dual specificity phosphatase 6 [Homo sapiens]
DUSP6 dual specificity phosphatase 6 [Homo sapiens]
Gene ID:1848

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847767	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 8, 2019)	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

SCV004847767

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 8, 2019)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847767.1

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

Description

The p.Ser22PhefsX8 variant in PMS2 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 22 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2.

#	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: Jun 23, 2024

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