The p.S144F variant (also known as c.431C>T), located in coding exon 5 of the RAD51D gene, results from a C to T substitution at nucleotide position 431. The serine at codon 144 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ClinVar Genomic variation as it relates to human health
NM_002878.4(RAD51D):c.431C>T (p.Ser144Phe)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002878.4(RAD51D):c.431C>T (p.Ser144Phe)
Variation ID: 141609 Accession: VCV000141609.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q12 17: 35107037 (GRCh38) [ NCBI UCSC ] 17: 33434056 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 29, 2017 Sep 16, 2024 Mar 20, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002878.4:c.431C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002869.3:p.Ser144Phe missense NM_001142571.2:c.491C>T NP_001136043.1:p.Ser164Phe missense NM_133629.3:c.145-556C>T intron variant NR_037711.2:n.457C>T non-coding transcript variant NC_000017.11:g.35107037G>A NC_000017.10:g.33434056G>A NG_031858.1:g.17833C>T LRG_516:g.17833C>T LRG_516t1:c.431C>T LRG_516p1:p.Ser144Phe - Protein change
- S144F, S164F
- Other names
- -
- Canonical SPDI
- NC_000017.11:35107036:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| RAD51D | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
34 | 1821 | |
| RAD51L3-RFFL | - | - | - | GRCh38 | - | 1800 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
May 8, 2023 | RCV000130201.15 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2024 | RCV000483361.7 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 20, 2024 | RCV000649709.11 | |
|
See cases
|
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 23, 2019 | RCV001196273.3 |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 22, 2019 | RCV001818310.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
|
Uncertain significance
(May 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185038.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.S144F variant (also known as c.431C>T), located in coding exon 5 of the RAD51D gene, results from a C to T substitution at nucleotide … (more)
The p.S144F variant (also known as c.431C>T), located in coding exon 5 of the RAD51D gene, results from a C to T substitution at nucleotide position 431. The serine at codon 144 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Mar 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005053994.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(Oct 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366839.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more)
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. (less)
Clinical Features:
Breast carcinoma (present)
|
|
|
Uncertain significance
(Feb 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002068573.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
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Uncertain significance
(Jun 03, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534816.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RAD51D c.431C>T (p.S144F) variant has been reported in heterozygosity in at least three individuals with breast cancer (PMID: 33471991). However, it was also reported … (more)
The RAD51D c.431C>T (p.S144F) variant has been reported in heterozygosity in at least three individuals with breast cancer (PMID: 33471991). However, it was also reported in a healthy control in the same study. This variant was observed in 2/34592 chromosomes in the Latino population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 141609). In silico tools suggest the impact of the variant on protein function is inconclusive and functional studies have not been performed. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
|
|
|
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Uncertain significance
(Aug 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774722.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Dec 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686455.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with phenylalanine at codon 144 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with phenylalanine at codon 144 of the RAD51D 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. In a large breast cancer case-control meta-analysis, this variant has been reported in 3/60463 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000055). This variant has been identified in 6/251472 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. (less)
|
|
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Uncertain significance
(Dec 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000771541.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 144 of the RAD51D protein (p.Ser144Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 144 of the RAD51D protein (p.Ser144Phe). This variant is present in population databases (rs587781875, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 141609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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. (less)
|
|
|
Uncertain significance
(Mar 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000567841.6
First in ClinVar: Apr 29, 2017 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with breast cancer and also in an … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with breast cancer and also in an unaffected control (PMID: 33471991); Identified in a patient with breast cancer who also harbored a pathogenic variant in BRCA2 (PMID: 35534704); This variant is associated with the following publications: (PMID: 30675060, 35534704, 33471991, 21111057, 14704354, 19327148) (less)
|
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Breast-ovarian cancer, familial, susceptibility to, 4
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228906.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 05-27-2015 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on … (more)
Variant interpreted as Uncertain significance and reported on 05-27-2015 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Hypermetropia (present) , Myopia (present)
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Myriad Genetics, Inc.
Date variant was reported to submitter: 2015-05-27
Testing laboratory interpretation: Uncertain significance
|
Comment:
Comment:
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Comment:
This missense variant replaces serine with phenylalanine at codon 144 of the RAD51D 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. In a large breast cancer case-control meta-analysis, this variant has been reported in 3/60463 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000055). This variant has been identified in 6/251472 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.
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 144 of the RAD51D protein (p.Ser144Phe). This variant is present in population databases (rs587781875, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 141609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with breast cancer and also in an unaffected control (PMID: 33471991); Identified in a patient with breast cancer who also harbored a pathogenic variant in BRCA2 (PMID: 35534704); This variant is associated with the following publications: (PMID: 30675060, 35534704, 33471991, 21111057, 14704354, 19327148)
Comment:
Variant interpreted as Uncertain significance and reported on 05-27-2015 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The p.S144F variant (also known as c.431C>T), located in coding exon 5 of the RAD51D gene, results from a C to T substitution at nucleotide position 431. The serine at codon 144 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Comment:
This missense variant replaces serine with phenylalanine at codon 144 of the RAD51D 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. In a large breast cancer case-control meta-analysis, this variant has been reported in 3/60463 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000055). This variant has been identified in 6/251472 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.
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 144 of the RAD51D protein (p.Ser144Phe). This variant is present in population databases (rs587781875, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 141609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with breast cancer and also in an unaffected control (PMID: 33471991); Identified in a patient with breast cancer who also harbored a pathogenic variant in BRCA2 (PMID: 35534704); This variant is associated with the following publications: (PMID: 30675060, 35534704, 33471991, 21111057, 14704354, 19327148)
Comment:
Variant interpreted as Uncertain significance and reported on 05-27-2015 by Lab Myriad Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Text-mined citations for rs587781875 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.