7-5973522-A-G

Variant names:

• chr7-5973522-A-G
• rs10000
• NM_000535.7:c.2466T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000535.7(PMS2):​c.2466T>C​(p.Leu822Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L822L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (91 hom., cov: 9)
  • Exomes 𝑓: 0.13 (2515 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:17
• Conservation: PhyloP100: -0.920
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-5973522-A-G is Benign according to our data. Variant chr7-5973522-A-G is described in ClinVar as Benign. ClinVar VariationId is 36690.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 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.2466T>C	p.Leu822Leu	synonymous	Exon 15 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2652T>C	p.Leu884Leu	synonymous	Exon 16 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2499T>C	p.Leu833Leu	synonymous	Exon 15 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.2466T>C	p.Leu822Leu	synonymous	Exon 15 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.1263T>C	p.Leu421Leu	synonymous	Exon 11 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.*107T>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.114 AC: 8266 AN: 72292 Hom.: 89 Cov.: 9

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0361

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.110 AC: 15089 AN: 136684 AF XY: 0.115

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.0587

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.0381

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.127 AC: 65729 AN: 515862 Hom.: 2515 Cov.: 6 AF XY: 0.129 AC XY: 35287 AN XY: 273858

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0490 AC: 715 AN: 14592

American (AMR) AF: 0.0632 AC: 1722 AN: 27268

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 2055 AN: 15814

East Asian (EAS) AF: 0.0319 AC: 883 AN: 27642

South Asian (SAS) AF: 0.139 AC: 7448 AN: 53416

European-Finnish (FIN) AF: 0.105 AC: 4354 AN: 41628

Middle Eastern (MID) AF: 0.145 AC: 302 AN: 2078

European-Non Finnish (NFE) AF: 0.146 AC: 44847 AN: 306402

Other (OTH) AF: 0.126 AC: 3403 AN: 27022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.114 AC: 8277 AN: 72368 Hom.: 91 Cov.: 9 AF XY: 0.115 AC XY: 3829 AN XY: 33250

African (AFR) AF: 0.0530 AC: 1008 AN: 19018

American (AMR) AF: 0.113 AC: 714 AN: 6338

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 292 AN: 1932

East Asian (EAS) AF: 0.0366 AC: 88 AN: 2404

South Asian (SAS) AF: 0.149 AC: 251 AN: 1682

European-Finnish (FIN) AF: 0.123 AC: 538 AN: 4374

Middle Eastern (MID) AF: 0.188 AC: 33 AN: 176

European-Non Finnish (NFE) AF: 0.146 AC: 5133 AN: 35046

Other (OTH) AF: 0.136 AC: 125 AN: 918

Alfa AF: 0.110 Hom.: 109

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	3	Lynch syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lynch syndrome 4 (2)
-	-	2	not provided (2)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.18
DANN	Benign	0.64
PhyloP100		-0.92
Mutation Taster		=100/0	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: rs10000; hg19: chr7-6013153; COSMIC: COSV56221454; COSMIC: COSV56221454;