VCV000650958.10 - ClinVar

NM_024675.4(PALB2):c.211+1G>T

Germline

Classification

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.

(4)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024675.4(PALB2):c.211+1G>T

Variation ID: 650958 Accession: VCV000650958.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p12.2 16: 23637849 (GRCh38) [ NCBI UCSC ] 16: 23649170 (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	Aug 14, 2019	Feb 14, 2024	Feb 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.211+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001407296.1:c.151+1G>T		splice donor
NM_001407297.1:c.211+1G>T		splice donor
NM_001407298.1:c.211+1G>T		splice donor
NM_001407299.1:c.211+1G>T		splice donor
NM_001407300.1:c.211+1G>T		splice donor
NM_001407301.1:c.211+1G>T		splice donor
NM_001407302.1:c.211+1G>T		splice donor
NM_001407304.1:c.-675+1G>T		splice donor
NM_001407305.1:c.-675+1G>T		splice donor
NM_001407306.1:c.-675+1G>T		splice donor
NM_001407307.1:c.-675+1G>T		splice donor
NM_001407308.1:c.-675+1G>T		splice donor
NM_001407309.1:c.-675+1G>T		splice donor
NM_001407310.1:c.-675+1G>T		splice donor
NM_001407311.1:c.-675+1G>T		splice donor
NM_001407312.1:c.-105+3261G>T		intron variant
NM_001407313.1:c.-105+3261G>T		intron variant
NM_001407314.1:c.48+3261G>T		intron variant
NC_000016.10:g.23637849C>A
NC_000016.9:g.23649170C>A
NG_007406.1:g.8509G>T
LRG_308:g.8509G>T
LRG_308t1:c.211+1G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000016.10:23637848:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1555462026 VarSome

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
Gene	OMIM	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.
PALB2		-	-	GRCh38 GRCh37	5913	5955

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.
Familial cancer of breast	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 17, 2022	RCV000806217.10
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 6, 2024	RCV001291546.4

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.
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001480064.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Breast carcinoma (present) Sex: female
Likely pathogenic (Dec 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580543.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM2_SUP	Number of individuals with the variant: 1 Sex: female
Likely pathogenic (Feb 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004242703.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Likely pathogenic (Oct 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000946204.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 32068069‚ 16199547‚ 17200668‚ 17200671‚ 17200672‚ 24136930‚ 25099575 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 650958). Disruption of this splice site has been observed in individual(s) with PALB2-related conditions (PMID: 32068069). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the PALB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). (less)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 650958). Disruption of this splice site has been observed in individual(s) with PALB2-related conditions (PMID: 32068069). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the PALB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel.	Kwong A	The Journal of molecular diagnostics : JMD	2020	PMID: 32068069
Breast-cancer risk in families with mutations in PALB2.	Antoniou AC	The New England journal of medicine	2014	PMID: 25099575
The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer.	Janatova M	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2013	PMID: 24136930
Fanconi anemia is associated with a defect in the BRCA2 partner PALB2.	Xia B	Nature genetics	2007	PMID: 17200672
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.	Reid S	Nature genetics	2007	PMID: 17200671
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.	Rahman N	Nature genetics	2007	PMID: 17200668
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs1555462026 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_024675.4(PALB2):c.211+1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555462026 ...