ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

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.

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)

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.