rs74902811

Variant names:

• chr7-5987233-G-A
• rs74902811
• NM_000535.7:c.1532C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5987233-G-A
• chr7-5987233-G-C
• chr7-5987233-G-T

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.1532C>T​(p.Thr511Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,614,052 control chromosomes in the GnomAD database, including 283 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. T511A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.024 (134 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (149 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:26 O:1
• Conservation: PhyloP100: -0.250
• Publications: 24 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: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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=0.0023566186).
• BP6: Variant 7-5987233-G-A is Benign according to our data. Variant chr7-5987233-G-A is described in ClinVar as Benign. ClinVar VariationId is 41704.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.1532C>T	p.Thr511Met	missense	Exon 11 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.1718C>T	p.Thr573Met	missense	Exon 12 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.1532C>T	p.Thr511Met	missense	Exon 11 of 15	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.1532C>T	p.Thr511Met	missense	Exon 11 of 15	ENSP00000265849.7
	PMS2	ENST00000406569.8	TSL:1	n.1532C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000514464.1
	PMS2	ENST00000382321.5	TSL:1	c.804-4242C>T		intron	N/A	ENSP00000371758.4

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3595 AN: 152122 Hom.: 128 Cov.: 32

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0324

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00811 AC: 2037 AN: 251308 AF XY: 0.00660

Gnomad AFR exome AF: 0.0813

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0291

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00333 AC: 4868 AN: 1461812 Hom.: 149 Cov.: 43 AF XY: 0.00302 AC XY: 2193 AN XY: 727194

African (AFR) AF: 0.0834 AC: 2791 AN: 33478

American (AMR) AF: 0.00380 AC: 170 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0290 AC: 1150 AN: 39698

South Asian (SAS) AF: 0.00117 AC: 101 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000187 AC: 208 AN: 1111992

Other (OTH) AF: 0.00705 AC: 426 AN: 60394

GnomAD4 genome AF: 0.0238 AC: 3620 AN: 152240 Hom.: 134 Cov.: 32 AF XY: 0.0236 AC XY: 1759 AN XY: 74420

African (AFR) AF: 0.0786 AC: 3264 AN: 41540

American (AMR) AF: 0.00713 AC: 109 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0323 AC: 167 AN: 5178

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68022

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.00840 Hom.: 24

Bravo AF: 0.0270

ESP6500AA AF: 0.0774 AC: 341

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00937 AC: 1138

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	-	5	Lynch syndrome 4 (5)
-	1	3	not provided (4)
-	-	2	Lynch syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.17
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.25
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.030	B
Vest4		0.12
MVP		0.39
MPC		0.039
ClinPred		0.00024	T
GERP RS		-3.2
Varity_R		0.014
gMVP		0.23
Mutation Taster		=99/1	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: rs74902811; hg19: chr7-6026864; COSMIC: COSV56223062;