chr16-23635172-A-G

Variant names:

• chr16-23635172-A-G
• rs878855098
• NM_024675.4:c.1374T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_024675.4(PALB2):​c.1374T>C​(p.Thr458Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.414
• Publications: 2 publications found

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-23635172-A-G is Benign according to our data. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635172-A-G is described in CliVar as Likely_benign. Clinvar id is 241526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.414 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1374T>C	p.Thr458Thr	synonymous_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1374T>C	p.Thr458Thr	synonymous_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Apr 12, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial cancer of breast Benign:1

Nov 10, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.2
DANN	Benign	0.67
PhyloP100		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878855098; hg19: chr16-23646493;