7-5987311-G-T

Variant names:

• chr7-5987311-G-T
• rs1805323
• NM_000535.7:c.1454C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.1454C>A​(p.Thr485Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,614,064 control chromosomes in the GnomAD database, including 5,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T485M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.052 (535 hom., cov: 31)
  • Exomes 𝑓: 0.057 (5319 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:22 O:1
• Conservation: PhyloP100: 0.0320
• Publications: 63 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004676789).
• BP6: Variant 7-5987311-G-T is Benign according to our data. Variant chr7-5987311-G-T is described in ClinVar as Benign. ClinVar VariationId is 41702.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

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.1454C>A	p.Thr485Lys	missense	Exon 11 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.1640C>A	p.Thr547Lys	missense	Exon 12 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.1454C>A	p.Thr485Lys	missense	Exon 11 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.1454C>A	p.Thr485Lys	missense	Exon 11 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.804-4320C>A		intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.1454C>A		non_coding_transcript_exon	Exon 11 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7903 AN: 152096 Hom.: 534 Cov.: 31

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0465

GnomAD2 exomes AF: 0.0801 AC: 20146 AN: 251466 AF XY: 0.0843

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0624

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.0890

Gnomad NFE exome AF: 0.0423

Gnomad OTH exome AF: 0.0676

GnomAD4 exome AF: 0.0575 AC: 84022 AN: 1461850 Hom.: 5319 Cov.: 44 AF XY: 0.0603 AC XY: 43855 AN XY: 727226

African (AFR) AF: 0.0170 AC: 569 AN: 33480

American (AMR) AF: 0.0235 AC: 1053 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 1702 AN: 26136

East Asian (EAS) AF: 0.370 AC: 14678 AN: 39700

South Asian (SAS) AF: 0.148 AC: 12735 AN: 86254

European-Finnish (FIN) AF: 0.0891 AC: 4759 AN: 53410

Middle Eastern (MID) AF: 0.0420 AC: 242 AN: 5768

European-Non Finnish (NFE) AF: 0.0397 AC: 44111 AN: 1111982

Other (OTH) AF: 0.0691 AC: 4173 AN: 60396

GnomAD4 genome AF: 0.0520 AC: 7908 AN: 152214 Hom.: 535 Cov.: 31 AF XY: 0.0563 AC XY: 4188 AN XY: 74406

African (AFR) AF: 0.0180 AC: 750 AN: 41556

American (AMR) AF: 0.0324 AC: 495 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1784 AN: 5164

South Asian (SAS) AF: 0.159 AC: 767 AN: 4826

European-Finnish (FIN) AF: 0.0877 AC: 929 AN: 10598

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2830 AN: 68008

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0503 Hom.: 856

Bravo AF: 0.0445

TwinsUK AF: 0.0367 AC: 136

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.0407 AC: 350

ExAC AF: 0.0801 AC: 9722

Asia WGS AF: 0.251 AC: 870 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0414

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	5	Lynch syndrome 4 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Lynch syndrome (3)
-	-	3	not provided (3)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0080
DANN	Benign	0.20
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.032
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.10
Sift	Benign	0.93	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.042
ClinPred		0.0026	T
GERP RS		-10
Varity_R		0.046
gMVP		0.21
Mutation Taster		=96/4	polymorphism (auto)

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: rs1805323; hg19: chr7-6026942; COSMIC: COSV56219377;