chr16-23607914-A-C

Variant names:

• chr16-23607914-A-C
• rs45516100
• NM_024675.4:c.3300T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024675.4(PALB2):​c.3300T>G​(p.Thr1100Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,614,080 control chromosomes in the GnomAD database, including 732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1100T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 31)
  • Exomes 𝑓: 0.028 (660 hom.)
• Consequence: PALB2 NM_024675.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 0.305
• Publications: 30 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: Ambry Genetics
• PALB2-related cancer predisposition

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

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PALB2-AS1 (HGNC:58305):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-23607914-A-C is Benign according to our data. Variant chr16-23607914-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.305 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.3300T>G	p.Thr1100Thr	synonymous	Exon 12 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3240T>G	p.Thr1080Thr	synonymous	Exon 11 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.3228T>G	p.Thr1076Thr	synonymous	Exon 11 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3300T>G	p.Thr1100Thr	synonymous	Exon 12 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2415T>G	p.Thr805Thr	synonymous	Exon 12 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.3306T>G	p.Thr1102Thr	synonymous	Exon 12 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3870 AN: 152138 Hom.: 72 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0237 AC: 5950 AN: 251488 AF XY: 0.0248

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0351

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0279 AC: 40855 AN: 1461824 Hom.: 660 Cov.: 32 AF XY: 0.0282 AC XY: 20473 AN XY: 727224

African (AFR) AF: 0.0165 AC: 551 AN: 33476

American (AMR) AF: 0.0175 AC: 781 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 932 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0258 AC: 2228 AN: 86254

European-Finnish (FIN) AF: 0.0195 AC: 1044 AN: 53420

Middle Eastern (MID) AF: 0.0610 AC: 352 AN: 5766

European-Non Finnish (NFE) AF: 0.0299 AC: 33267 AN: 1111966

Other (OTH) AF: 0.0281 AC: 1697 AN: 60388

GnomAD4 genome AF: 0.0254 AC: 3865 AN: 152256 Hom.: 72 Cov.: 31 AF XY: 0.0253 AC XY: 1885 AN XY: 74444

African (AFR) AF: 0.0172 AC: 716 AN: 41560

American (AMR) AF: 0.0268 AC: 410 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0239 AC: 115 AN: 4820

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10608

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2034 AN: 68014

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0266 Hom.: 40

Bravo AF: 0.0260

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0363

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	-	3	Familial cancer of breast (3)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	-	1	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
-	-	1	Fanconi anemia complementation group N (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.64
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs45516100; hg19: chr16-23619235;