rs587780046

Variant names:

• chr7-5982986-G-A
• rs587780046
• NM_000535.7:c.2012C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5982986-G-A
• chr7-5982986-G-C
• chr7-5982986-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001406866.1(PMS2):​c.2198C>T​(p.Thr733Met) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,515,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T733A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: PMS2 NM_001406866.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:22 B:6 O:1
• Conservation: PhyloP100: 5.70
• Publications: 15 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17239493).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000234 (319/1364466) while in subpopulation MID AF = 0.00143 (6/4200). AF 95% confidence interval is 0.000621. There are 1 homozygotes in GnomAdExome4. There are 169 alleles in the male GnomAdExome4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406866.1. 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.2012C>T	p.Thr671Met	missense	Exon 12 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.2198C>T	p.Thr733Met	missense	Exon 13 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.2012C>T	p.Thr671Met	missense	Exon 12 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.2012C>T	p.Thr671Met	missense	Exon 12 of 15	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.809C>T	p.Thr270Met	missense	Exon 8 of 11	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.1678+4101C>T		intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151324 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000190 AC: 32 AN: 168512 AF XY: 0.000219

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000234 AC: 319 AN: 1364466 Hom.: 1 Cov.: 22 AF XY: 0.000249 AC XY: 169 AN XY: 678008

African (AFR) AF: 0.0000332 AC: 1 AN: 30140

American (AMR) AF: 0.0000260 AC: 1 AN: 38394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.000187 AC: 7 AN: 37472

South Asian (SAS) AF: 0.0000620 AC: 5 AN: 80696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51042

Middle Eastern (MID) AF: 0.00143 AC: 6 AN: 4200

European-Non Finnish (NFE) AF: 0.000282 AC: 294 AN: 1040936

Other (OTH) AF: 0.0000884 AC: 5 AN: 56530

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151324 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 11 AN XY: 73844

African (AFR) AF: 0.0000489 AC: 2 AN: 40898

American (AMR) AF: 0.0000659 AC: 1 AN: 15186

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0000953 AC: 1 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.000180 AC: 21

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	8	-	not provided (8)
-	5	1	Lynch syndrome 4 (6)
-	4	1	Hereditary cancer-predisposing syndrome (5)
-	1	2	not specified (3)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Cancer or benign tumor (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 1 (1)
-	1	-	Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 (1)
-	-	-	Lynch syndrome;C5436817:Mismatch repair cancer syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.026	D
Polyphen		0.84	P
Vest4		0.29
MVP		0.92
MPC		2.6
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.041
gMVP		0.24
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs587780046; hg19: chr7-6022617;