7-152648889-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_005431.2(XRCC2):c.596T>C(p.Met199Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M199L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: XRCC2 NM_005431.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 5.62

Genes affected

XRCC2 (HGNC:12829): (X-ray repair cross complementing 2) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene is involved in the repair of DNA double-strand breaks by homologous recombination and it functionally complements Chinese hamster irs1, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105573624).
• BP6: Variant 7-152648889-A-G is Benign according to our data. Variant chr7-152648889-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182996.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000308 (45/1461878) while in subpopulation EAS AF= 0.000957 (38/39698). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4_exome. There are 22 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC2	NM_005431.2	c.596T>C	p.Met199Thr	missense_variant	3/3	ENST00000359321.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC2	ENST00000359321.2	c.596T>C	p.Met199Thr	missense_variant	3/3	1	NM_005431.2	P1
XRCC2	ENST00000495707.1	n.618T>C		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1	c.428T>C	p.Met143Thr	missense_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251410 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2016	This variant is denoted XRCC2 c.596T>C at the cDNA level, p.Met199Thr (M199T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. XRCC2 Met199Thr was not observed at a significant allele frequency in the 1000 Genomes Project. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. XRCC2 Met199Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether XRCC2 Met199Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 16, 2023	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 199 of the XRCC2 protein (p.Met199Thr). This variant is present in population databases (rs149099078, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on XRCC2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 21, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 04, 2021

DNA sequence analysis of the XRCC2 gene demonstrated a sequence change, c.596T>C, in exon 3 that results in an amino acid change, p.Met199Thr. This sequence change has been described in the gnomAD database with a frequency of 0.09% in the East Asian subpopulation (dbSNP rs149099078). The p.Met199Thr change affects a highly conserved amino acid residue located in a domain of the XRCC2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met199Thr substitution. This sequence change does not appear to have been previously described in individuals with XRCC2-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Met199Thr change remains unknown at this time. -

Fanconi anemia complementation group U Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Benign	0.84
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Benign	0.075	T
Sift4G	Uncertain	0.035	D
Polyphen		0.40	B
Vest4		0.71
MVP		0.57
MPC		0.25
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.33
gMVP		0.42

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: rs149099078; hg19: chr7-152345974;