7-6009173-G-C

Variant names:

• chr7-6009173-G-C
• rs3735296
• NM_000535.7:c.-154C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.-154C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,291,306 control chromosomes in the GnomAD database, including 13,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2217 hom., cov: 32)
  • Exomes 𝑓: 0.14 (11477 hom.)
• Consequence: PMS2 NM_000535.7 upstream_gene
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.140
• 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]

AIMP2 (HGNC:20609): (aminoacyl tRNA synthetase complex interacting multifunctional protein 2) The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex. [provided by RefSeq, May 2016]

AIMP2 Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 17

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 7-6009173-G-C is Benign according to our data. Variant chr7-6009173-G-C is described in ClinVar as Benign. ClinVar VariationId is 91280.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.-154C>G		upstream_gene	N/A	NP_000526.2
	AIMP2	NM_006303.4	MANE Select	c.-191G>C		upstream_gene	N/A	NP_006294.2
	PMS2	NM_001406866.1		c.-154C>G		upstream_gene	N/A	NP_001393795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.-154C>G		upstream_gene	N/A	ENSP00000265849.7
	AIMP2	ENST00000223029.8	TSL:1 MANE Select	c.-191G>C		upstream_gene	N/A	ENSP00000223029.3
	PMS2	ENST00000382321.5	TSL:1	c.-154C>G		upstream_gene	N/A	ENSP00000371758.4

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24671 AN: 151986 Hom.: 2212 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0662

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.136 AC: 155035 AN: 1139200 Hom.: 11477 Cov.: 15 AF XY: 0.137 AC XY: 79051 AN XY: 578990

African (AFR) AF: 0.223 AC: 5956 AN: 26718

American (AMR) AF: 0.0915 AC: 3641 AN: 39788

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4342 AN: 23626

East Asian (EAS) AF: 0.0755 AC: 2841 AN: 37652

South Asian (SAS) AF: 0.149 AC: 11653 AN: 78392

European-Finnish (FIN) AF: 0.174 AC: 8916 AN: 51242

Middle Eastern (MID) AF: 0.157 AC: 565 AN: 3596

European-Non Finnish (NFE) AF: 0.133 AC: 110197 AN: 828610

Other (OTH) AF: 0.140 AC: 6924 AN: 49576

GnomAD4 genome AF: 0.162 AC: 24679 AN: 152106 Hom.: 2217 Cov.: 32 AF XY: 0.163 AC XY: 12120 AN XY: 74362

African (AFR) AF: 0.229 AC: 9507 AN: 41494

American (AMR) AF: 0.108 AC: 1643 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3470

East Asian (EAS) AF: 0.0656 AC: 339 AN: 5168

South Asian (SAS) AF: 0.144 AC: 697 AN: 4824

European-Finnish (FIN) AF: 0.175 AC: 1853 AN: 10574

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9379 AN: 67986

Other (OTH) AF: 0.151 AC: 320 AN: 2114

Alfa AF: 0.0440 Hom.: 38

Bravo AF: 0.161

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.8
DANN	Benign	0.77
PhyloP100		0.14
PromoterAI		0.034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3735296; hg19: chr7-6048804;