7-6004044-C-T

Variant names:

• chr7-6004044-C-T
• rs587782176
• NM_000535.7:c.178G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000535.7(PMS2):​c.178G>A​(p.Asp60Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,433,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D60E) has been classified as Likely benign. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 5.75
• Publications: 1 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

Y_RNA (HGNC:):

ACMG classification

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 42 uncertain in NM_000535.7

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. 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.178G>A	p.Asp60Asn	missense	Exon 3 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.364G>A	p.Asp122Asn	missense	Exon 4 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.178G>A	p.Asp60Asn	missense	Exon 3 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.178G>A	p.Asp60Asn	missense	Exon 3 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.178G>A	p.Asp60Asn	missense	Exon 3 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.178G>A		non_coding_transcript_exon	Exon 3 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000360 AC: 9 AN: 250088 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 47 AN: 1433428 Hom.: 0 Cov.: 26 AF XY: 0.0000252 AC XY: 18 AN XY: 714796

African (AFR) AF: 0.00 AC: 0 AN: 32816

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 0.0000395 AC: 43 AN: 1088270

Other (OTH) AF: 0.0000675 AC: 4 AN: 59286

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	2	-	Lynch syndrome 4 (2)
-	2	-	not provided (2)
-	2	-	not specified (2)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)
-	1	-	Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)
-	1	-	PMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.26	T
Sift4G	Uncertain	0.022	D
Polyphen		0.86	P
Vest4		0.52
MutPred		0.36		Loss of ubiquitination at K59 (P = 0.1062)
MVP		0.95
MPC		0.26
ClinPred		0.90	D
GERP RS		5.5
PromoterAI		-0.0024	Neutral
Varity_R		0.52
gMVP		0.39
Mutation Taster		=47/53	disease causing

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: rs587782176; hg19: chr7-6043675;