16-23630140-C-G

Variant names:

• chr16-23630140-C-G
• rs45532440
• NM_024675.4:c.2014G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP1

This summary comes from the ClinGen Evidence Repository: The c.2014G>C variant in PALB2 is a missense variant predicted to cause a substitution of a glutamic acid by glutamine at amino acid 672 (p.Glu672Gln). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.02846 in non-Finnish European population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays (PMID:31636395, PMID:31757951, PMID:33964450); however, due to a lack of known positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA151230/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.022 (63 hom., cov: 32)
  • Exomes 𝑓: 0.028 (652 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign reviewed by expert panel B:30 O:1
• Conservation: PhyloP100: 0.103
• Publications: 59 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.2014G>C	p.Glu672Gln	missense	Exon 5 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.1954G>C	p.Glu652Gln	missense	Exon 4 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.2014G>C	p.Glu672Gln	missense	Exon 5 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.2014G>C	p.Glu672Gln	missense	Exon 5 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.1129G>C	p.Glu377Gln	missense	Exon 5 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.2020G>C	p.Glu674Gln	missense	Exon 5 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3367 AN: 152160 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0465

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0228 AC: 5725 AN: 251424 AF XY: 0.0241

Gnomad AFR exome AF: 0.00529

Gnomad AMR exome AF: 0.0154

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: 0.0289

GnomAD4 exome AF: 0.0277 AC: 40430 AN: 1461866 Hom.: 652 Cov.: 33 AF XY: 0.0279 AC XY: 20287 AN XY: 727238

African (AFR) AF: 0.00508 AC: 170 AN: 33480

American (AMR) AF: 0.0165 AC: 738 AN: 44724

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

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

South Asian (SAS) AF: 0.0259 AC: 2231 AN: 86258

European-Finnish (FIN) AF: 0.0195 AC: 1043 AN: 53404

Middle Eastern (MID) AF: 0.0609 AC: 351 AN: 5768

European-Non Finnish (NFE) AF: 0.0300 AC: 33313 AN: 1112002

Other (OTH) AF: 0.0273 AC: 1649 AN: 60396

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152278 Hom.: 63 Cov.: 32 AF XY: 0.0220 AC XY: 1638 AN XY: 74474

African (AFR) AF: 0.00592 AC: 246 AN: 41570

American (AMR) AF: 0.0253 AC: 387 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 161 AN: 3466

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4822

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0298 AC: 2030 AN: 68022

Other (OTH) AF: 0.0280 AC: 59 AN: 2106

Alfa AF: 0.0282 Hom.: 50

Bravo AF: 0.0224

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00706 AC: 31

ESP6500EA AF: 0.0315 AC: 271

ExAC AF: 0.0224 AC: 2718

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0362

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	Familial cancer of breast (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	not provided (4)
-	-	2	Malignant tumor of breast (2)
-	-	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	Ovarian cancer (1)
-	-	1	PALB2-related cancer predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.10
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.029
Sift	Benign	0.096	T
Sift4G	Benign	0.30	T
Polyphen		0.23	B
Vest4		0.046
MPC		0.085
ClinPred		0.0011	T
GERP RS		1.8
Varity_R		0.036
gMVP		0.18
Mutation Taster		=98/2	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: rs45532440; hg19: chr16-23641461; COSMIC: COSV55161919;