NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys) AND Breast-ovarian cancer, familial, susceptibility to, 4

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jan 27, 2026
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:: RCV000228533.22

Allele description [Variation Report for NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys)]

NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys)

Genes:

RAD51D:RAD51 paralog D [Gene - OMIM - HGNC]
RAD51L3-RFFL:RAD51L3-RFFL readthrough [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

17q12

Genomic location:

Preferred name:

NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys)

Other names:

p.S46C:TCT>TGT

HGVS:

NC_000017.11:g.35119118G>C
NG_031858.1:g.5752C>G
NG_054719.1:g.2540G>C
NM_001142571.2:c.137C>G
NM_002878.4:c.137C>GMANE SELECT
NM_133629.3:c.137C>G
NP_001136043.1:p.Ser46Cys
NP_002869.3:p.Ser46Cys
NP_002869.3:p.Ser46Cys
NP_598332.1:p.Ser46Cys
LRG_516t1:c.137C>G
LRG_516:g.5752C>G
LRG_516p1:p.Ser46Cys
NC_000017.10:g.33446137G>C
NM_002878.3:c.137C>G
NR_037711.2:n.282C>G
NR_037712.2:n.282C>G
p.S46C

Protein change:

S46C

Links:

dbSNP: rs587780102

Molecular consequence:

NM_001142571.2:c.137C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002878.4:c.137C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133629.3:c.137C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_037711.2:n.282C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_037712.2:n.282C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 4
Identifiers:: MONDO: MONDO:0013669; MedGen: C3280345; Orphanet: 145; OMIM: 614291

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000287698	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2026)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22986143, 25938944, 27616075, 32522261, 33630411, 35565380, 28492532
SCV000784997	Counsyl	no assertion criteria provided	Uncertain significance (Mar 15, 2017)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27616075, 25938944, 21822267, 22986143
SCV004017757	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Apr 6, 2023)	unknown	clinical testing	Citation Link,
SCV004208087	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 19, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005641839	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 10, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

Velázquez C, Lastra E, Avila Cobos F, Abella L, de la Cruz V, Hernando BA, Hernández L, Martínez N, Infante M, Durán M.

J Transl Med. 2020 Jun 10;18(1):232. doi: 10.1186/s12967-020-02391-z.

PubMed [citation]

PMID:: 32522261
PMCID:: PMC7288470

Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome.

Ferrer-Avargues R, Castillejo MI, Dámaso E, Díez-Obrero V, Garrigos N, Molina T, Codoñer-Alejos A, Segura Á, Sánchez-Heras AB, Castillejo A, Soto JL.

Cancer Commun (Lond). 2021 Mar;41(3):218-228. doi: 10.1002/cac2.12134. Epub 2021 Feb 25.

PubMed [citation]

PMID:: 33630411
PMCID:: PMC7968885

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000287698.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 46 of the RAD51D protein (p.Ser46Cys). This variant is present in population databases (rs587780102, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, multiple adenomatous polyps, and/or ovarian cancer (PMID: 22986143, 25938944, 27616075, 32522261, 33630411, 35565380). ClinVar contains an entry for this variant (Variation ID: 127882). 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 disruptive. Experimental studies have shown that this missense change affects RAD51D function (PMID: 35565380). 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.

#	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 Counsyl, SCV000784997.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

From Myriad Genetics, Inc., SCV004017757.1

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

Description

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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

From Baylor Genetics, SCV004208087.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV005641839.1

#	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 9, 2026

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Relating variation to medicine