rs199657566

chr8-89947826-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002485.5(NBN):c.1912T>C(p.Ser638Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,557,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S638Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: NBN NM_002485.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002125
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 0.116

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05363977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.1912T>C	p.Ser638Pro	missense_variant, splice_region_variant	12/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.1912T>C	p.Ser638Pro	missense_variant, splice_region_variant	12/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000260 AC: 6 AN: 230692 Hom.: 0 AF XY: 0.0000241 AC XY: 3 AN XY: 124702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000277 AC: 39 AN: 1405662 Hom.: 0 Cov.: 25 AF XY: 0.0000300 AC XY: 21 AN XY: 700566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000291

Gnomad4 OTH exome AF: 0.0000858

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000105 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000496 AC: 6

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 638 of the NBN protein (p.Ser638Pro). This variant is present in population databases (rs199657566, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 141273). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 29, 2020	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2021	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with a personal history of rectal cancer who also carried a PALB2 pathogenic variant (Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 27535533, 32668560, 24349281) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 18, 2022	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 07, 2020	This missense variant replaces serine with proline at codon 638 of the NBN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 6/230692 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2022	The p.S638P variant (also known as c.1912T>C), located in coding exon 12 of the NBN gene, results from a T to C substitution at nucleotide position 1912. The serine at codon 638 is replaced by proline, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast and ovarian cancer (Wang J et al. Cancer Med, 2019 05;8:2074-2084; Wang J et al. Cancer Med, 2019 05;8:2074-2084). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 18, 2019

Variant summary: NBN c.1912T>C (p.Ser638Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.7e-05 in 225126 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in one individual affected with colorectal and lung cancer (Yurgelun_2017). The report does not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial ovarian cancer Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The NBN p.Ser638Pro variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with intrahepatic cholangiocarcinoma (Wang 2013). The variant was also identified in dbSNP (ID: rs199657566) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl). The variant was not identified in Cosmic, LOVD 3.0 or the Zhejiang University database. The variant was identified in control databases in 6 of 225126 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 32486 chromosomes (freq: 0.00003), European in 4 of 99228 chromosomes (freq: 0.00004), and South Asian in 1 of 28658 chromosomes (freq: 0.00004); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ser638 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Ser638Pro variant occurs in the 3rd last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was predicted to be damaging to Nbs1 function by loss of the nuclear localization of Mre11 and leading to deficiency in DNA double strand break repair (Wang 2013). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	12
Dann	Benign	0.96
DEOGEN2	Benign	0.066	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.040	N;N;.
REVEL	Benign	0.034
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.28
MutPred		0.14		Loss of phosphorylation at S638 (P = 0.0649);.;.;
MVP		0.55
MPC		0.084
ClinPred		0.033	T
GERP RS		-3.4
Varity_R		0.053
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.024
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: rs199657566; hg19: chr8-90960054;