7-6003684-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000535.7(PMS2):c.353+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,492,036 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

PMS2
NM_000535.7 splice_region, intron

Scores

Splicing: ADA: 0.002117

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:7O:1

Conservation

PhyloP100: -1.41

Publications

1 publications found

Variant links:

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

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-6003684-T-C is Benign according to our data. Variant chr7-6003684-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237913.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS2	NM_000535.7	MANE Select	c.353+6A>G	splice_region intron	N/A	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.539+6A>G	splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.353+6A>G	splice_region intron	N/A	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.353+6A>G	splice_region intron	N/A	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.353+6A>G	splice_region intron	N/A	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.353+6A>G	splice_region intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000597

AC:

AN:

234546

AF XY:

0.0000310

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000141

AC:

189

AN:

1339884

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

673022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31400

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25482

East Asian (EAS)

AF:

0.00

AC:

AN:

39102

South Asian (SAS)

AF:

0.00

AC:

AN:

83792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4166

European-Non Finnish (NFE)

AF:

0.000186

AC:

189

AN:

1015972

Other (OTH)

AF:

0.00

AC:

AN:

56568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000535

Hom.:

Bravo

AF:

0.0000718

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary cancer-predisposing syndrome (2)

Lynch syndrome 4 (2)

not specified (2)

Breast and/or ovarian cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome (1)

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)

Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.6

(source)

DANN

Benign

0.69

PhyloP100

-1.4

PromoterAI

0.060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0021

dbscSNV1_RF

Benign

0.22

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over