ClinVar Genomic variation as it relates to human health
NM_032043.3(BRIP1):c.790C>T (p.Arg264Trp)
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.
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(3); Benign(1); Likely benign(16)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_032043.3(BRIP1):c.790C>T (p.Arg264Trp)
Variation ID: 128195 Accession: VCV000128195.62
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.2 17: 61808595 (GRCh38) [ NCBI UCSC ] 17: 59885956 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 9, 2014 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032043.3:c.790C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_114432.2:p.Arg264Trp missense NC_000017.11:g.61808595G>A NC_000017.10:g.59885956G>A NG_007409.2:g.59965C>T LRG_300:g.59965C>T LRG_300t1:c.790C>T LRG_300p1:p.Arg264Trp - Protein change
- R264W
- Other names
- p.R264W:CGG>TGG
- Canonical SPDI
- NC_000017.11:61808594: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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0.00140 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00071
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
Trans-Omics for Precision Medicine (TOPMed) 0.00094
1000 Genomes Project 0.00140
The Genome Aggregation Database (gnomAD) 0.00104
1000 Genomes Project 30x 0.00125
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 | ||
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HI score
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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. |
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BRIP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5541 | 5595 |
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. |
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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2021 | RCV000116164.20 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV000120409.28 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 18, 2016 | RCV000409223.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 27, 2017 | RCV000411226.16 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 7, 2023 | RCV000515771.17 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV000679792.37 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001082519.15 | |
Benign/Likely benign (2) |
no assertion criteria provided
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- | RCV001269494.10 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 21, 2023 | RCV001798362.11 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 28, 2023 | RCV004528813.1 |
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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Likely benign
(Dec 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000150073.12
First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001284961.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Jun 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043641.2
First in ClinVar: Jan 03, 2022 Last updated: Feb 04, 2024 |
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Likely benign
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001477824.2
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501678.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
BRIP1: BP1
Number of individuals with the variant: 2
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Likely benign
(Aug 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000246815.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Likely benign
(Jan 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537408.1
First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017 |
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Likely benign
(Mar 28, 2018)
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criteria provided, single submitter
Method: research
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Hereditary Breast Carcinoma
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000611880.2
First in ClinVar: Dec 08, 2017 Last updated: Feb 23, 2019 |
Comment:
The BRIP1 variant designated as NM_032043.2:c.790C>T (p.Arg264Trp) is now classified as likely benign. The variant is present in approximately 1 in 500 individuals in European … (more)
The BRIP1 variant designated as NM_032043.2:c.790C>T (p.Arg264Trp) is now classified as likely benign. The variant is present in approximately 1 in 500 individuals in European and African populations (exac.broadinstitute.org). This population frequency is not consistent with a high-risk cancer variant. In addition, there are no reports of pathogenic missense variants in this BRIP1 protein domain. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128195). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. (less)
Family history: yes
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140786.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Feb 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889226.3
First in ClinVar: Sep 14, 2018 Last updated: Jan 03, 2022 |
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Likely benign
(Jan 08, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529235.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jul 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm of ovary
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489858.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Jul 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group J
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489857.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016917.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Uncertain significance
(Mar 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019480.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
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.
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Fanconi anemia complementation group J
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166689.14
First in ClinVar: Jun 15, 2014 Last updated: Feb 28, 2024 |
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Likely benign
(Mar 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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BRIP1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000807157.2
First in ClinVar: Sep 14, 2018 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Dec 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000183754.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Likely benign
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010848.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551199.6
First in ClinVar: Jul 30, 2022 Last updated: Feb 14, 2024 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Breast Cancer
Affected status: yes
Allele origin:
germline
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Center of Medical Genetics and Primary Health Care
Accession: SCV001449150.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549885.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRIP1 p.Arg264Trp variant was identified in 55 of 46810 proband chromosomes (frequency: 0.001) from Italian, American, British and Colombian individuals or families with a … (more)
The BRIP1 p.Arg264Trp variant was identified in 55 of 46810 proband chromosomes (frequency: 0.001) from Italian, American, British and Colombian individuals or families with a wide spectrum of cancers (in population based studies, unselected for family history): BRCA1/2 negative, male/female breast cancer, prostate cancer, ovarian cancer, Lynch syndrome associated cancer and/or polyps, CRC, pancreatic cancer, hereditary prostate cancer and Fanconi anemia; and was present in 44 of 29724 control chromosomes (frequency: 0.001) from healthy individuals (Silvestri_2011_21165771, Bodian_2014_24728327, Hu_2016_26483394, Yurgelun_2015_25980754, Tung_20016_26976419, Seal_2006_17033622, Easton_2016_26921362, Levitus_2005_16116423, Pearlman_2016_27978560, Ramus_2015_26315354, Cock-Rada_2017_28528518, Ray_2009_19935797). In one prostate cancer family, the variant was identified in two out of three cases and was not present in the unaffected brother of the proband (Ray_2009_19935797). In 1 male proband with breast cancer, diagnosed at 76 yrs of age, DNA extracted from the micro-dissected breast tumor sample showed that no loss of the wild-type allele had occurred in tumor cells (Silvestri_2011_21165771). The variant was identified in dbSNP (ID: rs28997569) “With Likely benign allele”, ClinVar (classified likely benign by Invitae, Ambry Genetics, Genetic Services Laboratory (University of Washington), Counsyl, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and GeneDx, and classification not provided by ITMI), Clinvitae (5x) and Zhejiang Colon Cancer Database, and was not identified in Cosmic or MutDB. The variant was also identified in control databases in 229 of 276746 chromosomes at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 17 of 24030 chromosomes (freq: 0.0007), “Other” in 11 of 6452 chromosomes (freq: 0.002), Latino in 15 of 34408 chromosomes (freq: 0.0004), European Non-Finnish in 145 of 126288 chromosomes (freq: 0.001), Ashkenazi Jewish in 28 of 10142 chromosomes (freq: 0.003), European Finnish in 7 of 25786 chromosomes (freq: 0.0003), and South Asian in 6 of 30782 chromosomes (freq: 0.0002); it was not observed in the East Asian population. The p.Arg264 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084561.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. | Easton DF | Journal of medical genetics | 2016 | PMID: 26921362 |
BRIP1, a potential candidate gene in development of non-BRCA1/2 breast cancer. | Ouhtit A | Frontiers in bioscience (Elite edition) | 2016 | PMID: 26709662 |
Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. | Hu C | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2016 | PMID: 26483394 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology. | De Rocco D | Haematologica | 2014 | PMID: 24584348 |
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
Mutation analysis of BRIP1 in male breast cancer cases: a population-based study in Central Italy. | Silvestri V | Breast cancer research and treatment | 2011 | PMID: 21165771 |
Absence of truncating BRIP1 mutations in chromosome 17q-linked hereditary prostate cancer families. | Ray AM | British journal of cancer | 2009 | PMID: 19935797 |
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. | Seal S | Nature genetics | 2006 | PMID: 17033622 |
The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. | Levitus M | Nature genetics | 2005 | PMID: 16116423 |
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Text-mined citations for rs28997569 ...
HelpRecord last updated Jun 02, 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.