rs2066456

Positions:

• chr2-189863781-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The ENST00000441310.7(PMS1):​c.1895A>G​(p.Asn632Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000324 in 1,608,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PMS1 ENST00000441310.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 5.20

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

LOC105373796 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005708903).
• BP6: Variant 2-189863781-A-G is Benign according to our data. Variant chr2-189863781-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 135058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS1	NM_000534.5	c.1895A>G	p.Asn632Ser	missense_variant	10/13	ENST00000441310.7	NP_000525.1
LOC105373796	XR_001739151.2	n.98+750T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.1895A>G	p.Asn632Ser	missense_variant	10/13	1	NM_000534.5	ENSP00000406490	P1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152188 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00587

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000412 AC: 103 AN: 250258 Hom.: 1 AF XY: 0.000251 AC XY: 34 AN XY: 135462

Gnomad AFR exome AF: 0.00531

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000181 AC: 263 AN: 1455784 Hom.: 0 Cov.: 29 AF XY: 0.000153 AC XY: 111 AN XY: 724710

Gnomad4 AFR exome AF: 0.00588

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000271

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152306 Hom.: 0 Cov.: 30 AF XY: 0.00165 AC XY: 123 AN XY: 74468

Gnomad4 AFR AF: 0.00587

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.00178

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2020	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T;D;T;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;.;D;D;D;T;T;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.0	.;.;.;.;M;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	.;.;N;.;N;N;N;N
REVEL	Benign	0.059
Sift	Uncertain	0.015	.;.;D;.;D;D;D;D
Sift4G	Benign	0.14	.;T;T;T;T;T;T;T
Polyphen		0.25, 0.28	.;.;.;B;B;.;.;.
Vest4		0.19, 0.19, 0.20, 0.21, 0.25
MVP		0.99
MPC		0.095
ClinPred		0.020	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.084

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

Publications

LitVar

Other links and lift over

dbSNP: rs2066456; hg19: chr2-190728507;