NM_002485.5(NBN):c.1262T>C (p.Leu421Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jan 10, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000115780.18

Allele description [Variation Report for NM_002485.5(NBN):c.1262T>C (p.Leu421Ser)]

NM_002485.5(NBN):c.1262T>C (p.Leu421Ser)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.1262T>C (p.Leu421Ser)

Other names:

p.L421S:TTG>TCG

HGVS:

NC_000008.11:g.89955418A>G
NG_008860.1:g.34254T>C
NM_001024688.3:c.1016T>C
NM_002485.5:c.1262T>CMANE SELECT
NP_001019859.1:p.Leu339Ser
NP_002476.2:p.Leu421Ser
NP_002476.2:p.Leu421Ser
LRG_158t1:c.1262T>C
LRG_158:g.34254T>C
LRG_158p1:p.Leu421Ser
NC_000008.10:g.90967646A>G
NC_000008.9:g.91036822A>G
NM_001024688.2:c.1016T>C
NM_002485.4:c.1262T>C
p.L421S

Protein change:

L339S

Links:

dbSNP: rs104895032

NCBI 1000 Genomes Browser:

rs104895032

Molecular consequence:

NM_001024688.3:c.1016T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002485.5:c.1262T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000183761	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 21, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20805886, 26315354, 29300386 Citation Link,
SCV000680451	GeneID Lab - Advanced Molecular Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 7, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000886692	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Sep 28, 2018)	germline	clinical testing
SCV002536582	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Benign (Feb 13, 2021)	germline	curation	Citation Link,
SCV002819156	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
Ashkenazi Jewish	germline	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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]

PMID:: 20805886
PMCID:: PMC2923613

Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.

Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, Fraser L, Gentry-Maharaj A, Hayward J, Philpott S, Anderson C, Edlund CK, Conti D, Harrington P, Barrowdale D, Bowtell DD, Alsop K, Mitchell G; AOCS Study Group., Cicek MS, Cunningham JM, Fridley BL, et al.

J Natl Cancer Inst. 2015 Aug 27;107(11). doi:pii: djv214. 10.1093/jnci/djv214. Print 2015 Nov.

PubMed [citation]

PMID:: 26315354
PMCID:: PMC4643629

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000183761.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneID Lab - Advanced Molecular Diagnostics, SCV000680451.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Ashkenazi Jewish	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From True Health Diagnostics, SCV000886692.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002536582.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV002819156.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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