7-5992026-A-C

Variant names:

• chr7-5992026-A-C
• rs530021751
• NM_000535.7:c.935T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001322011.2(PMS2):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMS2 NM_001322011.2 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 0 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

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 43 pathogenic variants. Next in-frame start position is after 51 codons. Genomic position: 5989860. Lost 0.091 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322011.2. 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.935T>G	p.Met312Arg	missense	Exon 9 of 15	NP_000526.2	P54278-1
	PMS2	NM_001322011.2		c.2T>G	p.Met1?	start_lost	Exon 9 of 15	NP_001308940.1
	PMS2	NM_001322012.2		c.2T>G	p.Met1?	start_lost	Exon 9 of 15	NP_001308941.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.935T>G	p.Met312Arg	missense	Exon 9 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.803+5300T>G		intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.935T>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449224 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721836

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100556

Other (OTH) AF: 0.00 AC: 0 AN: 59954

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.16
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.94	L
PhyloP100		2.3
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.51
Sift	Benign	0.34	T
Sift4G	Benign	0.87	T
Polyphen		0.90	P
Vest4		0.66
MutPred		0.61		Loss of loop (P = 0.0804)
MVP		0.60
MPC		0.097
ClinPred		0.13	T
GERP RS		0.32
Varity_R		0.69
gMVP		0.60
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs530021751; hg19: chr7-6031657;