NM_058216.3(RAD51C):c.3G>A (p.Met1Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000216075.12

Allele description [Variation Report for NM_058216.3(RAD51C):c.3G>A (p.Met1Ile)]

NM_058216.3(RAD51C):c.3G>A (p.Met1Ile)

Gene:

RAD51C:RAD51 paralog C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_058216.3(RAD51C):c.3G>A (p.Met1Ile)

HGVS:

NC_000017.11:g.58692646G>A
NG_023199.1:g.5045G>A
NG_047169.1:g.4434C>T
NM_002876.4:c.3G>A
NM_058216.3:c.3G>AMANE SELECT
NP_002867.1:p.Met1Ile
NP_478123.1:p.Met1Ile
LRG_314t1:c.3G>A
LRG_314:g.5045G>A
NC_000017.10:g.56770007G>A
NM_058216.1:c.3G>A
NM_058216.2:c.3G>A
NR_103872.2:n.45G>A
NR_103873.1:n.74G>A

Protein change:

M1I

Links:

dbSNP: rs769053886

NCBI 1000 Genomes Browser:

rs769053886

Molecular consequence:

NM_002876.4:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_058216.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_002876.4:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_058216.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_103872.2:n.45G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_103873.1:n.74G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Recent activity

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cytochrome oxidase subunit 1, partial (mitochondrion) [Diapriidae sp. ASWAV054-0...
cytochrome oxidase subunit 1, partial (mitochondrion) [Diapriidae sp. ASWAV054-08]
gi|411168212|gb|AFW10444.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274466	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31173646, 33471991 Citation Link,
SCV000686349	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12966089, 31173646, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274466

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 11, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000686349

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 21, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Identification of functional domains in the RAD51L2 (RAD51C) protein and its requirement for gene conversion.

French CA, Tambini CE, Thacker J.

J Biol Chem. 2003 Nov 14;278(46):45445-50. Epub 2003 Sep 8.

PubMed [citation]

PMID:: 12966089

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000274466.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.M1? variant (also known as c.3G>A), located in coding exon 1 of the RAD51C gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 9 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000686349.7

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

Description

This variant affects the translation start codon of the RAD51C gene and may result in an absent or non-functional protein product. However, an in-frame methionine 9 codons downstream may function as an alternative start codon and is located before the first known functional domain (RAD51B/RAD51D/XRCC3 interacting domain at amino acids 79-136) of the RAD51C protein. A functional study has shown that the RAD51C protein produced from this downstream methionine can function similarly to the wild type protein (PMID: 12966089). This variant has been reported in an individual affected with breast cancer (PMID: 31173646). This variant has been identified in 1/31396 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.

#	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: Oct 26, 2024

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