rs376042544

Variant names:

• chr7-5987486-G-A
• rs376042544
• NM_000535.7:c.1279C>T
• PMS2 p.Arg427Cys

Your query was ambiguous. Multiple possible variants found:

• chr7-5987486-G-A
• chr7-5987486-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4BP6

The NM_000535.7(PMS2):c.1279C>T (p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000211 (AC=34) in the gnomAD database across 1,613,976 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00023. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R427H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 185424); p.R427L: Uncertain_significance (ClinVar VariationId 2828578, 1 star); p.R427= (synonymous): Likely_benign (ClinVar VariationId 1133919, 2 stars); p.R427= (synonymous): Benign/Likely_benign (ClinVar VariationId 818786, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 4.03
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, 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: Labcorp Genetics (formerly Invitae), G2P
• 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.00023 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000336 by highest known P/LP ClinVar AF 0.000336) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 NM_000535.7	MANE Select	c.1279C>T p.Arg427Cys	missense	Exon 11 of 15	Prot: NP_000526.2 UniProt:
	PMS2 NM_001406866.1		c.1465C>T p.Arg489Cys	missense	Exon 12 of 16	Prot: NP_001393795.1 UniProt:
	PMS2 NM_001322014.2		c.1279C>T p.Arg427Cys	missense	Exon 11 of 15	Prot: NP_001308943.1 UniProt:

PMS2 NM_000535.7

MANE Select

HGVSc / HGVSpc.1279C>Tp.Arg427Cys

Exon rankExon 11 of 15

missense

Prot: NP_000526.2UniProt: P54278-1

PMS2 NM_001406866.1

HGVSc / HGVSpc.1465C>Tp.Arg489Cys

Exon rankExon 12 of 16

missense

Prot: NP_001393795.1UniProt: A0A8V8TNX6

PMS2 NM_001322014.2

HGVSc / HGVSpc.1279C>Tp.Arg427Cys

Exon rankExon 11 of 15

missense

Prot: NP_001308943.1UniProt: A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 ENST00000265849.12	TSL:1MANE Select	c.1279C>T p.Arg427Cys	missense	Exon 11 of 15	Prot: ENSP00000265849.7 UniProt:
	PMS2 ENST00000382321.5	TSL:1	c.804-4495C>T	intron	Intron 7 of 10	Prot: ENSP00000371758.4 UniProt:
	PMS2 ENST00000406569.8	TSL:1	n.1279C>T	non_coding_transcript_exon	Exon 11 of 13	Prot: ENSP00000514464.1 UniProt:

PMS2 ENST00000265849.12

TSL:1MANE Select

HGVSc / HGVSpc.1279C>Tp.Arg427Cys

Exon rankExon 11 of 15

missense

Prot: ENSP00000265849.7UniProt: P54278-1

PMS2 ENST00000382321.5

TSL:1

HGVSc / HGVSpc.804-4495C>T

Exon rankIntron 7 of 10

intron

Prot: ENSP00000371758.4UniProt: P54278-2

PMS2 ENST00000406569.8

TSL:1

HGVSc / HGVSpn.1279C>T

Exon rankExon 11 of 13

non_coding_transcript_exon

Prot: ENSP00000514464.1UniProt: P54278-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000105	AC:16	Hom:0	AN:152154	Cov:31
GnomAD2 exomes	AF: 0.0000279	AC:7	Hom:	AN:250898	Cov:
GnomAD4 exome	AF: 0.0000123	AC:18	Hom:0	AN:1461822	Cov:34
GnomAD4 genome	AF: 0.000105	AC:16	Hom:0	AN:152154	Cov:31
TOPMed (Bravo)	AF: 0.000121	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000116	AC:5	Hom:0	AN:42990	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122718	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000819	9	109956	0.0000322	6	186232

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	3	-	not provided (3)
-	2	-	Lynch syndrome 4 (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	not specified (1)
-	1	-	PMS2-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	20
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Benign	0.033
GPN-Star LLR	N/A	-3.3
GPN-Star score	N/A	3.3
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.23	D
Mutation Taster	N/A	56/44	polymorphism
MutationAssessor	Benign	1.4	L
PhyloP100	Uncertain	4.0
popEVE	Benign	-3.7
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.085	T
Varity_R	N/A	0.065
VESM-3B	Benign	-5.8

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.18
Pangolin gain	Benign	0.18	Position offset: -13
SpliceAI score (max)	Benign	0.11	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs376042544;

hg19: chr7-6027117;

COSMIC: COSV99764665;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar