NM_005732.4(RAD50):c.494C>A (p.Pro165His) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Sep 19, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_005732.4(RAD50):c.494C>A (p.Pro165His)]

NM_005732.4(RAD50):c.494C>A (p.Pro165His)

RAD50:RAD50 double strand break repair protein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_005732.4(RAD50):c.494C>A (p.Pro165His)
  • NC_000005.10:g.132579445C>A
  • NG_021151.1:g.27522C>A
  • NG_021151.2:g.27469C>A
  • NM_005732.4:c.494C>AMANE SELECT
  • NP_005723.2:p.Pro165His
  • LRG_312t1:c.494C>A
  • LRG_312:g.27469C>A
  • LRG_312p1:p.Pro165His
  • NC_000005.8:g.131943036C>A
  • NC_000005.9:g.131915137C>A
  • NM_005732.3:c.494C>A
Protein change:
dbSNP: rs104895044
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_005732.4:c.494C>A - missense variant - [Sequence Ontology: SO:0001583]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000628301Invitaecriteria provided, single submitter
Uncertain significance
(Feb 28, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001185168Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Sep 19, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.

Offer SM, Pan-Hammarström Q, Hammarström L, Harris RS.

PLoS One. 2010 Aug 18;5(8):e12260. doi: 10.1371/journal.pone.0012260.

PubMed [citation]

Details of each submission

From Invitae, SCV000628301.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)


This sequence change replaces proline with histidine at codon 165 of the RAD50 protein (p.Pro165His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs104895044, ExAC 0.001%) but has not been reported in the literature in individuals with a RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 126996). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV001185168.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)


The p.P165H variant (also known as c.494C>A), located in coding exon 4 of the RAD50 gene, results from a C to A substitution at nucleotide position 494. The proline at codon 165 is replaced by histidine, an amino acid with similar properties. This variant has been reported in an individual with immunoglobulin A deficiency (IgAD)/common variable immunodeficiency (CVID), who was also identified to carry a p.R327H alteration on the other RAD50 allele (Offer SM et al. PLoS ONE, 2010 Aug;5:e12260). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Jan 25, 2021

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