rs587778613

Variant names:

• chr2-189864105-C-A
• rs587778613
• NM_000534.5:c.2219C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-189864105-C-A
• chr2-189864105-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000534.5(PMS1):​c.2219C>A​(p.Ser740Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S740F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.60
• Publications: 0 publications found

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]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000300477 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30482507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.2219C>A	p.Ser740Tyr	missense_variant	Exon 10 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.2219C>A	p.Ser740Tyr	missense_variant	Exon 10 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461352 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727024

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111574

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.029	T;T;T;.;.;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.
PhyloP100		3.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	.;N;N;N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.010	.;D;D;D;D;D
Sift4G	Uncertain	0.028	D;D;T;T;D;T
Polyphen		0.083	.;.;B;.;.;.
Vest4		0.28
MutPred		0.40		.;.;Loss of loop (P = 0.0374);.;.;.;
MVP		0.94
MPC		0.093
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.17
gMVP		0.38
Mutation Taster		=86/14	polymorphism

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: rs587778613; hg19: chr2-190728831;