Submissions for variant NM_002485.5(NBN):c.1871G>A (p.Arg624His)

gnomAD frequency: 0.00002  dbSNP: rs587782297

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131180	SCV000186127	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.R624H variant (also known as c.1871G>A), located in coding exon 12 of the NBN gene, results from a G to A substitution at nucleotide position 1871. The arginine at codon 624 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is poorly 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.
GeneDx	RCV000212751	SCV000211457	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197335	SCV000254770	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 624 of the NBN protein (p.Arg624His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 142193). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131180	SCV000685739	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 624 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/261390 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000197335	SCV002012400	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-09-22	criteria provided, single submitter	clinical testing	The NBN c.1871G>A (p.Arg624His) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-90960095-C-T). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Nijmegan breakage syndrome or NBN-associated cancers. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Genome-Nilou Lab	RCV000197335	SCV002044528	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131180	SCV002536622	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
Baylor Genetics	RCV003467165	SCV004199609	uncertain significance	Aplastic anemia	2023-08-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000197335	SCV001455019	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-04-14	no assertion criteria provided	clinical testing