rs12532895

Variant names:

• chr7-6003755-G-A
• rs12532895
• NM_000535.7:c.288C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-6003755-G-A
• chr7-6003755-G-C
• chr7-6003755-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001406875.1(PMS2):​c.-197C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,602,532 control chromosomes in the GnomAD database, including 5,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.047 (510 hom., cov: 32)
  • Exomes 𝑓: 0.047 (4605 hom.)
• Consequence: PMS2 NM_001406875.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 0.685
• Publications: 23 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-6003755-G-A is Benign according to our data. Variant chr7-6003755-G-A is described in ClinVar as Benign. ClinVar VariationId is 91350.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406875.1. 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.288C>T	p.Ala96Ala	synonymous	Exon 4 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406875.1		c.-197C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001393804.1
	PMS2	NM_001322015.2		c.-197C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001308944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.288C>T	p.Ala96Ala	synonymous	Exon 4 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.288C>T	p.Ala96Ala	synonymous	Exon 4 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.288C>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7192 AN: 152018 Hom.: 509 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0437

GnomAD2 exomes AF: 0.0804 AC: 19273 AN: 239762 AF XY: 0.0819

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0866

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.0834

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0600

GnomAD4 exome AF: 0.0470 AC: 68116 AN: 1450394 Hom.: 4605 Cov.: 29 AF XY: 0.0498 AC XY: 35930 AN XY: 722026

African (AFR) AF: 0.0172 AC: 575 AN: 33446

American (AMR) AF: 0.0815 AC: 3646 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 362 AN: 26120

East Asian (EAS) AF: 0.357 AC: 14130 AN: 39628

South Asian (SAS) AF: 0.146 AC: 12588 AN: 86112

European-Finnish (FIN) AF: 0.0840 AC: 3727 AN: 44384

Middle Eastern (MID) AF: 0.0338 AC: 187 AN: 5534

European-Non Finnish (NFE) AF: 0.0266 AC: 29492 AN: 1110242

Other (OTH) AF: 0.0566 AC: 3409 AN: 60216

GnomAD4 genome AF: 0.0473 AC: 7200 AN: 152138 Hom.: 510 Cov.: 32 AF XY: 0.0526 AC XY: 3913 AN XY: 74352

African (AFR) AF: 0.0192 AC: 797 AN: 41552

American (AMR) AF: 0.0536 AC: 817 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.343 AC: 1774 AN: 5172

South Asian (SAS) AF: 0.157 AC: 756 AN: 4818

European-Finnish (FIN) AF: 0.0869 AC: 916 AN: 10546

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1986 AN: 68016

Other (OTH) AF: 0.0499 AC: 105 AN: 2106

Alfa AF: 0.0300 Hom.: 36

Bravo AF: 0.0427

Asia WGS AF: 0.243 AC: 844 AN: 3478

EpiCase AF: 0.0275

EpiControl AF: 0.0274

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Lynch syndrome 4 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lynch syndrome (2)
-	-	2	not provided (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.8
DANN	Benign	0.81
PhyloP100		0.69
PromoterAI		0.021	Neutral
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs12532895; hg19: chr7-6043386; COSMIC: COSV56219896; COSMIC: COSV56219896;